Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9]O>>[Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH3:9])=[O:4]
Reactant: CC(C)C(Br)C(=O)O
Reactant: CO
Product: COC(=O)C(Br)C(C)C
Temperature: 25 °C

Procedure:
2-Bromo-3-methylbutyric acid (3.65 g, 20 mmole) was esterified in refluxing methanol containing 2 mL concentrated sulfuric acid for 22 hours. After cooling to room temperature, volatiles were evaporated and the residue was taken up in 50 mL of water and extracted with Et2O. The ether layer was washed with 5% aq. NaHCO3, water brine, and dried over Na2SO4. The desired material was obtained after filtration and removal of volatiles; homogeneous by TLC in 4/1 hexane/EtOAc.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[N:14][O:15][CH2:16][CH2:17][OH:18])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[N:14][O:15][CH2:16][CH2:17][O:18][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1ccc(-c2ccccc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc(-c4ccccc4)nc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 390 mg of 2-(2-phenyl-5-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 10), 576 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 422 mg of triphenylphosphine and 280 mg of diethyl azodicarboxylate, 671 mg of the title compound were obtained as a crystalline powder, melting at 146°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([OH:14])=O)=[C:5]2[OH:15].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:14])=[C:5]2[OH:15]
Reactant: O=C(O)c1ncc2ccc(Br)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1ncc2ccc(Br)cc2c1O
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-hydroxyisoquinoline-3-carboxylic acid (Preparation 8, 0.4 g), 4-chlorobenzylamine (0.219 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g) in DMF (20 mL) is stirred at room temperature until judged complete. The solution is then poured into ice water and the resulting solid collected and dried.
Reaction SMILES: [CH2:1]([C@H:8]([NH:16]C(=O)OC(C)(C)C)[C@@H:9]([OH:15])[C@H:10]([CH:12]1[CH2:14][CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CO>[NH2:16][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:15])[C@H:10]([CH:12]1[CH2:13][CH2:14]1)[OH:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1
Yield: 50.8 %

Procedure:
A solution of 2.0 g (6.23 mmol) of tert-butyl [(1S,2R,3S)-1-benzyl-3-cyclopropyl-2,3-dihydroxypropyl]carbamate in 20 ml of methanol was treated with 20 ml of 2N hydrochloric acid and the solution was heated to 500 for 90 minutes. After cooling, the solution was neutralized by the addition of 40 ml of 1N sodium hydroxide solution and evaporated to dryness on a rotary evaporator under reduced pressure. The residue was partitioned between water and methylene chloride. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. There was obtained 0.7 g of (1S,2R,3S)-3-amino-1-cyclopropyl-4-phenyl-1,2-butanediol as white crystalline solid, MS: 150 (M-C4H8O)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[C:20]3[N:21]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:22]([N:24]4[CH2:29][CH2:28][O:27][C@@H:26]5[CH2:30][CH2:31][CH2:32][C@@H:25]45)=[N:23][C:19]=3[CH:18]=[C:17](Cl)[N:16]=2)=[CH:13][C:12]([Cl:42])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:44]([N:46](C)C)=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[C:20]3[N:21]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:22]([N:24]4[CH2:29][CH2:28][O:27][C@@H:26]5[CH2:30][CH2:31][CH2:32][C@@H:25]45)=[N:23][C:19]=3[CH:18]=[C:17]([C:44]#[N:46])[N:16]=2)=[CH:13][C:12]([Cl:42])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N(C)C
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4OCc4ccccc4)c32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cc(Cl)cnc4OCc4ccccc4)c32)CC1
Temperature: 90 °C

Procedure:
4-[2-(benzyloxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic, 450 mg, 0.74 mmol), zinc cyanide (43 mg, 0.37 mmol) and Pd(PPh3)4 (128 mg, 0.11 mmol) were placed in a dry vial. Degassed DMA (4 mL) was added to the reaction, and the reaction was placed under an atmosphere of Ar, sealed, and heated at 90° C. for 12 hours. The reaction was then cooled to room temperature, and cold water was added slowly. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded 4-[2-(benzyloxy)-5-chloropyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a racemic mixture. The enantiomers were separated on a chiral OD column using 2% IPA/98% heptanes. MS ES calc'd. for C34H37ClN6O2 [M+H]+ 597. found 597.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([C@@H:33]1[O:35][C@H:34]1[CH2:36]O)[CH2:30][CH2:31][CH3:32]>C(Cl)(Cl)Cl>[CH2:29]([C@@H:33]1[O:35][C@H:34]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(O)c3)cn2)cc1
Reactant: CCCC[C@@H]1O[C@H]1CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(OC[C@@H]4O[C@H]4CCCC)c3)cn2)cc1

Procedure:
The synthesis is carried out analogously to Example 1 from 5-(3-hydroxyphenyl)-2-(4-octyloxyphenyl)pyrimidine and (2S, 3S )-3-butyloxiran-2-ylmethanol. ##STR44## [α]D20 (CHCl3)=-14.27
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:14]([OH:16])[CH3:15]>>[CH2:14]([O:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[CH3:15]
Reactant: CCO
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccc(C(=O)NC)cn1
Yield: 100 %

Procedure:
To a solution of 6-chloro-N-methylnicotinamide (500 mg, 2.93 mmol) in ethanol (10 mL), sodium hydride (purity 50%) (176 mg, 7.33 mmol) was added under ice-cold conditions. The resultant mixture was heated to reflux for 8 hours. After completion of the reaction, the reaction solution was concentrated in vacuo, then filtered, washed with water and ethyl acetate, and then dried. 6-Ethoxy-N-methylnicotinamide (556 mg, yield >100%) was obtained as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9](=[O:16])[NH:10]2.Br[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([O:16][CH2:28][CH3:29])=[N:10]2
Reactant: CCBr
Reactant: COC(=O)Cc1cc(C)cc2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1nc2cc(C)cc(CC(=O)OC)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 40 °C

Procedure:
A mixture of [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl]acetic acid methyl ester (1.0 g), bromoethane (0.24 mL), potassium carbonate (1.1 g) and N,N-dimethylformamide (10 mL) was heated at 40° C. for 17 hours. The mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 1:5 by volume) gave title compound as a gum, 0.28 g.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.C[O:39][CH2:40][C:41](O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:40]([O:22][CH:13]1[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/[C:12]/1=[CH:11]\[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:39])[CH3:41]
Reactant: COCC(=O)O
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of Compound 20b (37 mg, 0.13 mmol), DCC (26.7 mg, 0.13 mmol), and DMAP (31.6 mg, 0.26 mmol) in dry CH2Cl2 (20 mL) cooled in an ice-water bath was added methoxyacetic acid (17.5 mg, 0.19 mmol) followed by stirring at room temperature for 2 hours. The reaction mixture was filtered through a short plug of Celite with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 30.1 mg (65 percent) of Compound 30b: pale yellow oil; Rf=0.38 (20 percent EtOAc in hexane); IR (neat) 2932, 2239,2229, 1756, 1182, 1126 cm−1; 1H NMR (300 MHz, CDCl3) δ8.32 (d, J=7.29 Hz, 1H), 8.14-8.00 (m, 1H), 7.92-7.81 (m, 2H), 7.58-7.44 (m, 3H), 7.50 (s, 1H), 6.33 (t, J=1.05 Hz, 1H), 4.15 and 4.13 (AB q, J=16.50 Hz, 2H), 3.48 (s, 3H), 2.55-2.20 (m, 4H), 2.00-1.60 (m, 4H); 13C NMR (75 MHz, CDCl3) δ170.4, 134.2, 133.4, 132.8, 132.2, 129.8, 129.3, 127.1, 127.0, 126.5, 125.9, 124.1, 123.3, 103.5, 94.4, 80.8, 79.0, 70.6, 70.2, 60.1, 28.2, 28.1, 22.5, 21.4; MS (+CI) m/z (relative intensity) 359 (M+H+, 4), 269 (100); HRMS (+EI) calcd for C24H22O3 (M+) 358.1569, found 358.1574.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:14]([N:16]([C:18]1[CH:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]([CH3:34])[CH3:33])=[CH:27][C:26]=2[N+:35]([O-])=O)[N:21]=[CH:20][N:19]=1)[CH3:17])=[O:15]>CO.ClC1C=CC=CC=1.O=[Pt]=O>[NH2:35][C:26]1[CH:27]=[C:28]([CH2:31][N:32]([CH3:34])[CH3:33])[CH:29]=[CH:30][C:25]=1[NH:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]([N:16]([CH3:17])[C:14]([N:13]([C:3]2[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])[CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])=[O:15])[CH:23]=1
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(CN(C)C)cc3[N+](=O)[O-])ncn2)c1Cl
Agent: O=[Pt]=O
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(CN(C)C)cc3N)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-2-nitro-phenylamino)-pyrimidin-4-yl]-3-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-urea (100 g, 0.15 mmol) in MeOH (10 mL) was added 4 drops of chlorobenzene and then PtO2 (30 mg, 30% wt). The solution was stirred under hydrogen atmosphere at room temperature overnight. The reaction was filtered and concentrated. The residue was taken to the next step without further purification. MS (ESI): 650 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].F[C:17]1[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>CS(C)=O>[C:6]([O:5][C:3]([N:10]1[CH2:14][CH2:13][CH:12]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:11]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2)C1
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
To a suspension of NaH (0.17 g, 4.4 mmol, 1.1 equiv) in DMSO (4 mL) at rt was added (3S)-1-Boc-3-pyrrolidinol (0.75 g, 4.0 mmol, 1.00 equiv) in one portion. After stirring for 20 min, 3-fluoronitrobenzene (0.51 g, 3.6 mmol, 0.90 equiv) was added drop wise and the resulting suspension was stirred an additional 1.5 hours at rt. The reaction mixture was quenched with the addition of saturated, aqueous NH4Cl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Purification of the crude residue by chromatography (30% ethyl acetate in hexanes) afforded 3-(3-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as a bright yellow oil (0.676 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CCc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(CCc2ccccc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 46.5 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-phenylbutanoic acid (252.0 mg) and ethyl 4-aminophenylacetate hydrochloride (184.3 mg) were condensed in THF (4 ml) in the presence of triethylamine (384.9 μl) and pivaloyl chloride (140.4 μl), and then the resulting crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (170.5 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[N:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[C:14]2[OH:21]>C(O)(=O)C>[Br:1][C:15]1[CH:16]=[N:17][C:18]2[C:13]([C:14]=1[OH:21])=[N:12][C:11]([O:10][CH3:9])=[CH:20][CH:19]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nccc(O)c2n1
Solvent: CC(=O)O
Product: COc1ccc2ncc(Br)c(O)c2n1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
N-Bromosuccinimide (263 mg, 1.48 mmol, 1.3 eq) is added at 15° C. to a stirred solution of 6-methoxy-[1,5]naphthyridin-4-ol (200 mg, 1.14 mmol, 1.0 eq) in acetic acid (3 mL). After 30 minutes stirring at 15° C., the reaction mixture is allowed to come at room temperature and the resulting cake is filtered, washed with acetic acid and dried to afford 3-bromo-6-methoxy-[1,5]naphthyridin-4-ol as an off-white solid (280 mg, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 90 °C
Yield: 103.6 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 1.0 g) and lithium hydroxide monohydrate (0.96 g) in dioxane (16 mL) and water (14 mL) was stirred and heated at 90° C. for 1 hour. After cooling, the mixture was concentrated under vacuum and the residue was diluted with water and neutralised to pH7 with formic acid. The mixture was then extracted with ethyl acetate, dried (Na2SO4) and filtered and the filtrate was evaporated to dryness to give (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylic acid (0.97 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH3:22])=[O:10].Br[CH2:24][C:25]1[CH:26]=[C:27]([C:30]#[N:31])[S:28][CH:29]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH3:22])=[O:10])[O:8][CH2:24][C:25]1[CH:26]=[C:27]([C:30]#[N:31])[S:28][CH:29]=1
Reactant: N#Cc1cc(CBr)cs1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(O)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2csc(C#N)c2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (2-Fluoro-4-hydroxy-phenyl)-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone and 4-bromomethyl-thiophene-2-carbonitrile [CAS 186552-07-8]. MS (ES+) m/e 428.3
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([CH:17]=[CH:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1>CO.[Pd]>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=4)[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(C=Cc4ccncc4)cc3c21
Agent: [Pd]
Solvent: CO
Product: CC(C)Cn1cnc2c(N)nc3ccc(CCc4ccncc4)cc3c21
Reaction time: 168 h
Yield: 18 %

Procedure:
1-(2-Methylpropyl)-8-(2-pyridin-4-ylvinyl)-1H-imidazo[4,5-c]-quinolin-4-amine (2.1 g, 6.1 mmol) was treated according to the method described in Example 123; the reaction was allowed to run for seven days. An analysis by proton nuclear magnetic resonance spectroscopy indicated the presence of starting material in the purified product. The product mixture was dissolved in methanol (100 mL), and 10% palladium on carbon (200 mg) was added. The reaction was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for four days, and the product was isolated as described in Example 123. The crude product was purified by flash column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from acetonitrile to provide 380 mg of 1-(2-methylpropyl)-8-(2-pyridin-4-ylethyl)-1H-imidazo[4,5-c]-quinolin-4-amine as pale, yellow crystals, mp 221-224° C.
Reaction SMILES: S1C2C=CC=CC=2C(=[O:10])S1.OO.C(Cl)(Cl)Cl.[S:17]1(=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[S:18]1>FC(F)(F)C(O)=O>[S:17]1(=[O:10])(=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[S:18]1
Reactant: O=C1SS(=O)c2ccccc21
Reactant: O=c1ssc2ccccc12
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C1SS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3H-1,2-Benzodithiol-3-one (39.2 g, 0.23 mole) in trifluoroacetic acid (250 mL) was added 40 mL of a 30% aqueous solution of hydrogen peroxide. Cooling was necessary to maintain the internal reaction temperature between 40°-45° C. After 30 minutes, an additional 40 mL of 30% H2O2 was added and the reaction mixture was heated to ensure an internal reaction temperature of 40°-45° C. 30 minutes later, the last portion of 30% H2O2 (40 mL) was added under the same temperature conditions and the rate of the reaction was monitored by TLC (CHCl3) until the disappearance of the slow moving sulfoxide byproduct, i.e., 3H-1,2-benzodithiol-3-one 1-oxide (90 minutes). The reaction mixture was then filtered and the filtrate was added onto 3.5 L of crushed ice. The white precipitate was filtered through a 600 mL fritted glass funnel of coarse porosity and thoroughly washed with water until the filtrate was neutral and free of peroxides. The solid material was then transferred into a 500 mL separatory funnel to which was added dichloromethane (200 mL) and a 1% solution of sodium bisulfite (100 mL). After vigorous shaking, the organic phase was decanted and washed with water (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the amorphous solid was dried under vacuum. The crude compound (20.8 g) was dissolved in boiling dichloromethane (ca. 70 mL). Hexanes (ca. 50 mL) was added, and the boiling solution was allowed to cool to ambient temperature and then kept in the refrigerator at 10° C. The crystalline material was collected by filtration, washed with cold hexanes and dried under vacuum.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cc(F)ccc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.50 g, 0.855 mmol) and (S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.216 g, 1.027 mmol) in DMF (10 ml) was added sodium hydride (0.051 g, 1.283 mmol) and the resulting yellow mixture was stirred at rt. After 3 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water then brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 10 CV) to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.1481 g, 0.222 mmol, 26.0% yield) as a red oil. LCMS (M+H) calcd for C37H52FN4O6: 667.38. found: 667.6.