Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:35])[C@H:11]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[NH:12][C:13](=[O:24])[CH:14]([CH2:19][S:20]C(=O)C)[CH2:15][CH2:16][CH2:17][NH2:18].[OH-].[Na+].[H][H]>CO>[NH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH2:19][SH:20])[C:13]([NH:12][C@H:11]([C:10]([OH:35])=[O:9])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:24]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(CCCN)CSC(C)=O
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCCCC(CS)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
To a solution of N-(2-acetylthiomethyl-5-aminopentanoyl)-L-tryptophane methyl ester trifluoroacetate (3 g) in methanol (60 ml) N sodium hydroxide (60 ml) is added. After four hours the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. After washing with water, the N-(5-amino-2-mercaptomethylpentanoyl-L-tryptophane is eluted with pyridine-acetic acid buffer at pH 6.5.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([C:9]1[S:13][C:12](/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCC#Cc1ccc(C=O)s1
Product: CCCCCCC#Cc1ccc(/C=C/C(=O)O)s1
Yield: 93.5 %

Procedure:
Reaction of 5-(1-octynyl)-2-thiophene carboxaldehyde (880 mg, 4 mmole) with malonic acid as described in Example 2 yielded 0.98 g (93.5%) of the title compound after recrystallization from hexane mp 79° C.; νmax (mull) 2600 (broad), 1690, 1670, 1610, 940, 845, 800; δ(CDCl3) 0.90(3H, t, J=6 Hz), 1.50(8H, m), 2.40(2H, t, J=6 Hz), 6.15(1H, d, J=15 Hz), 7.05(1H, d, J=4.5 Hz), 7.13(1H, d, J=4.5 Hz), 7.85(1H, d, J=15 Hz), 11.3(1H, bs). M+ 262.1022 C15H15O2S requires 262.1027. Found; C, 68.96; H, 7.14; C15H15O2S requires; C, 68.68; H, 6.92.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2)=[O:4].[CH:16]12[N:23]([C:24]([O-:26])=[O:25])[CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2>>[O:15]=[C:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5][C:3]([CH2:2][N:18]2[CH2:19][CH:20]3[N:23]([C:24]([O:26][C:7]([CH3:11])([CH3:8])[CH3:6])=[O:25])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[O:4])[NH:10]1
Reactant: O=C(CCl)Nc1cccc2c1CC(=O)N2
Reactant: O=C([O-])N1C2CCC1CNC2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(CC(=O)Nc1cccc3c1CC(=O)N3)C2

Procedure:
The subtitle compound was prepared from the product of step (i) (0.24 g) and 1,1-dimethyl, 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.26 g) by the method of Example 19 step (i) Yield: 0.8 g
Reaction SMILES: [O:1]=[C:2]1[CH:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH:5]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][NH:3]1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[O:1]=[C:2]1[CH:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH:5]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][N:3]1[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCC(c2cccs2)SCC1N1C(=O)c2ccccc2C1=O
Product: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Following the procedure described in Example 42(f), 1.6 g of 5-oxo-6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepine [prepared as described in step (e) above] was treated with t-butyl bromoacetate to give 1.15 g of the title compound as crystals, melting at 183°-184° C.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1=CCCCC1
Reactant: OCc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CCN(CC)CC
Product: OCc1ccccc1C1CCCCC1
Yield: 42 %

Procedure:
According to example 61, 10.0 g of 2-iodobenzyl alcohol was treated with 25 mL of cyclohexene (Aldrich) using 0.96 g of Pd(OAc)2, 2.60 g of tri-ortho-tolylphosphine, and 6.6 mL of Et3N at 110° C. for 48 h. The resulting olefin mixture was hydrogenated for 6.5 h using 0.36 g of 5% Pt(C) in MeOH to afford 3.37 g (42%) of 2-cyclohexyl benzyl alcohol as a light yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH2:7]([NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: CCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCNCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-octylamine (0.35 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 6 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-octyl)-(3-(napthalen-2-yloxy)propyl)amine, solid, m.p. 109° C., (yield 0.63 gm, 89%).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]>C1COCC1>[CH3:1][NH:2][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Methylamine (4.5 ml of 2.0 M solution in THF) was added to a stirred solution of 2-chloro-1,3-dinitrobenzene (0.90 g, 4.4 mmol) in 40 ml of THF and the mixture was stirred for 30 min. The reaction was quenched by the addition of water and ether. The aqueous layer was separated and extracted twice with ether. The combined organic extracts were washed with saturated NaHCO3, brine and dried over magnesium sulfate. Filtration, removal of solvent and purification of residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to gave 0.80 g (91%) of product.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:17]1([C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCCBr)cc2)cc1
Reactant: C1COCCN1
Product: Fc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCCN3CCOCC3)cc2)cc1
Yield: 92 %

Procedure:
3.25 g (7 mmoles) of 1-[4-(2-bromoethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-propene are reacted with morpholine as described in Example 1. The product is crystallized from hexane. 3.03 g (92%) of the aimed compound are obtained; m.p.: 95°-96° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CON(C)[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][C:13]=1[CH3:19].[NH4+].[Cl-]>C1COCC1>[CH3:19][C:13]1[C:12]([C:11]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:20])=[CH:17][CH:16]=[C:15]([CH3:18])[N:14]=1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccc(C)nc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cncn2C)c(C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (360 mg, 2.24 mmol) was added THF and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropyl magnesium chloride-LiCl complex (1.3 M, 2.3 mL, 2.98 mmol) which resulted in a white suspension. The reaction mixture was stirred at 0° C. for 30 min, and a THF (2 mL) solution of N-methoxy-N,2,6-trimethylnicotinamide (522 mg, 2.69 mmol, Intermediate 40, step a) was introduced and the mixture was allowed to warm to room temperature for 3 hours and then heated to 50° C. for 20 hours. The contents were cooled to room temperature, poured into a saturated NH4Cl solution and extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography on silica gel (25-50% Acetonitrile-DCM increasing gradient to 5% MeOH-DCM) afforded the title compound as a pale yellowish solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5](=[NH:14])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].Cl[CH2:19][CH:20]=O.C(=O)(O)[O-].[Na+]>CC(O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])[CH:19]=[CH:20][N:14]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccccc1NC(=N)c1cccc(I)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccccc1-n1ccnc1-c1cccc(I)c1

Procedure:
To a 500 mL round bottom flask was added 3-iodo-N-(o-tolyl)benzimidamide (7.77 g, 23.11 mmol), 2-chloroacetaldehyde (5.87 ml, 46.2 mmol), sodium bicarbonate (3.88 g, 46.2 mmol), and 100 mL 2-propanol. The reaction mixture was heated to reflux under nitrogen for 5 hours. The reaction mixture was concentrated, water was added, and the mixture extracted three times with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 40 and 50% ethyl acetate/hexane (4.6 g, 55%).
Reaction SMILES: C([O:8][C:9]([C:11]1([N:19]([CH:37]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.O>[CH2:42]([O:41][C:39]([CH2:38][CH2:37][N:19]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:11]1([C:9]([OH:10])=[O:8])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:40])[CH3:43]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: [H][H]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN(C1(C(=O)O)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of (4.4 mmol) of the product of step D in 25 mL of ethanol is treated with 2.5 g of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi of hydrogen for 48 hours. The catalyst is removed by filtration and washed with ethanol (4×25 mL). The filtrate and washings are combined and concentrated under vacuum to crude product.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[N:17]([C:2]2[C:6]3[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=3[S:4][N:3]=2)[N:16]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(C)n(-c2nsc3ccc([N+](=O)[O-])cc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
A mixture of 3-chloro-5-nitrobenzisothiazole (5.3 g, mmol), 3,5-dimethylpyrazole (2.40 g, 25.0 mmol) and pyridine is stirred overnight at reflux, cooled to room temperature and diluted with ethyl acetate. The resultant mixture is filtered and the filtrate is washed with three portions of 10% hydrochloric acid and one portion of water. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound (2.85 g, 43.8%) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:12][C:4]1[N:3]=[C:2]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Solvent: c1ccncc1
Product: COc1ccc(CNc2cc(C(F)(F)F)cc(Cl)n2)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethyl-pyridine (5.04 g, 23.3 mmol) in pyridine (10 mL) was treated with 4-methoxybenzylamine (9.19 mL, 70.0 mmol) and heated to 110° C. for 26 h. The mixture was cooled, and pyridine (8 mL) was removed in vacuo. The remaining material was diluted with water (50 mL) and extracted twice with EtOAc (75 mL, and 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 115-g SEPRA Si 35 SPE column (Flow rate=35 mL/min; Eluent=EtOAc-hexanes, 1:99 for 15 min, then 1:99 to 1:9 over 40 min, 1:9 for 2 min, then 1:9 to 1:4 over 20 min) to yield (6-chloro-4-trifluoromethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine as a colorless oil, which solidified upon standing. 1H-NMR (400 MHz, CDCl3) δ: 7.26 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.77 (s, 1H), 6.44 (s, 1H), 5.21 (br. s., 1H), 4.44 (d, J=5.6 Hz, 2H), 3.80 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calculated for C14H12N2OClF3: 317.1 (M+H); Measured: 317.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:19]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1

Procedure:
N-tert-Butyl-4-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.69) (0.40 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.39 g, 1.5 mmol) according to the general procedure VI. Obtained as a light brown solid (0.64 g) which was subsequently deprotected.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@@H:26]4[CH2:30][C:29](=[O:31])[NH:28][CH2:27]4)[CH3:25])=[N:10][C:11](C4C=C5C(CC(=O)N5)=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH:50]4[CH2:52][CH:48]([O:49]4)[CH2:47]3)=[CH:42][CH:41]=2)O1>>[CH:50]12[CH2:52][CH:48]([O:49]1)[CH2:47][N:46]([C:43]1[CH:42]=[CH:41][C:40]([C:11]3[N:10]=[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:27][NH:28][C:29](=[O:31])[CH2:30]4)[CH3:25])[C:8]4[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:5]=[N:6][C:7]=4[CH:12]=3)=[CH:45][CH:44]=1)[CH2:51]2
Reactant: CC1(C)OB(c2ccc(N3CC4CC(C3)O4)cc2)OC1(C)C
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)O4)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 41 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)indolin-2-one:, using instead 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-oxa-3-azabicyclo[3.1.1]heptane (123.7 mg, 0.41 mmol) to afford 51.2 mg (41%) of (4R)-4-((1R)-1-((6-(4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)phenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.21 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.55 (s, 1H), 6.79 (d, J=8.7 Hz, 2H), 5.57 (m, 1H), 4.71 (m, 2H), 3.50 (m, 6H), 3.21 (m, 2H), 2.83 (m, 1H), 2.32 (m, 2H), 1.91 (m, 1H), 1.39 (d, J=6.2 Hz, 3H), 1.14 (m, 4H). MS (ESI+) m/z 460.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.Cl>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]([C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A 100-mL round bottomed flask fitted with a nitrogen inlet and magnetic stir bar was charged with (S)-tert-butyl 7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (4.75 g, 14.52 mmol), dichloromethane (50 mL), pyridine (1.996 mL, 24.68 mmol), and cyclopropanecarbonyl chloride (1.976 mL, 21.77 mmol). The reaction mixture was stirred at rt for 2 h and then 1 M aqueous HCl solution (25 mL) was added. The organic layer was separated and concentrated under reduced pressure to afford (S)-tert-butyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (5.72 g, 99%) as a solid, which was used directly in next step. MS (ESI, pos. ion) m/z 395, 397 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][OH:20]>C(Cl)Cl.[OH-].[Na+]>[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:17][C@@H:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][OH:20])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1Cc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1Cc1ccccc1
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
At 0° C., 2.1 g (9.2 mmol) of 2-benzylbenzoyl chloride dissolved in a little methylene chloride were added dropwise to 1.3 g (8.6 mmol) of (S)-2-amino-3-phenylpropan-1-ol in 35 ml of methylene chloride and 20 ml of 2M aqueous sodium hydroxide solution. The mixture was stirred for about 30 min. The organic phase was separated off, dried and concentrated under reduced pressure. 2.7 g (91%) of the product were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN
Reactant: ClCCCCOc1cccnc1
Solvent: CO
Product: CNCCCCOc1cccnc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
The 4-chloro-1-(3-pyridyloxy)butane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.47 g (75.5%) of an oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)C.[NH3:25]>CO.ClCCl>[CH2:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([NH2:25])=[O:3])=[CH:6][CH:7]=2)[N:16]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCc1ccnc(-c2ccc(C(=O)OCC)cc2)n1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1

Procedure:
4.4 g. of 4-(4-n-heptylpyrimid-2-yl)-benzoic acid ethyl ester dissolved in 50 ml. of a methanol-dichloromethane (1:1) mixture are treated with 30 ml. of liquid ammonia in a laboratory autoclave and then heated to 90° for 5 hours (pressure: 16 atmospheres). The reaction mixture is evaporated to dryness and the poorly soluble amide separated from the unreacted educt, whereby there is obtained 4-(4-n-heptylpyrimid-2yl)-benzoic acid amide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:17][O:16][CH2:15][CH2:14][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: COCCBr
Reactant: Cc1ccc2ccc(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1ccc2ccc(C)nc2c1
Temperature: 70 °C
Yield: 56.6 %

Procedure:
A mixture of 2-methylquinolin-7-ol (0.20 g, 1.3 mmol), 1-bromo-2-methoxyethane (0.24 mL, 2.5 mmol) and potassium carbonate (0.52 g, 3.8 mmol) in acetone (5.0 mL, 1.3 mmol) was heated at 70° C. for 12 hours. The cooled reaction mixture was diluted with water (10 mL) extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-50% ethyl acetate/hexanes) to provide title compound (0.16 g, 60%).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19].BrC1C=CC(NC2N=C(Cl)C=CC=2C(O)=[O:32])=C(F)C=1.C[Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:5]2[NH:6][C:7](=[O:32])[CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:20])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 93 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-chloronicotinic acid methyl ester: To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloronicotinic acid (5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N2 was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise until the bubbling caused by gas evolution ceased. Solids precipitated out of solution. The reaction was allowed to stir for 1 hour. Excess (trimethylsilyl)diazomethane was quenched by the dropwise addition of glacial acetic acid. The precipitated solids were filtered and washed with methanol. The filtrate was concentrated to a smaller volume and additional solids precipitated out of solution that were filtered and washed with methanol. The solids were combined and dried under vacuum to yield 4.82 g (93%) of pure desired product as a dark pink solid.