Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[O:3]1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:25]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:3]1)(=[O:27])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(O)O2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Reaction time: 1 h

Procedure:
To a stirring solution of (±)2-hydroxy-5-(p-toluenesulfonyloxymethyl)-tetrahydrofuran (example 58) (4.20 g, 15.44 mmol), pyridine (2.75 mL, 33.97 mmol) and DMAP (catalytic) in methylene chloride (100 mL) at rt was added acetic anhydride (2.91 mL, 30.88 mmol). After stirring the solution for 1 h, it was washed with water (50 mL), 1N HCl (50 mL), saturated NaHCO3 (50 mL), dried (MgSO4) and concentrated to give the title compound as a 1:1 mixture of cis and trans isomers (4.85 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](O)=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27].C(Cl)(=O)C([Cl:31])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([Cl:31])=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27]
Reactant: Cn1cc(-c2cc(C(=O)O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(C(=O)Cl)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of Example 10 (0.24 g, 0.67 mmol) in dichloromethane (10 mL) was treated with oxalyl chloride (0.17 g, 1.33 mmol) and dimethylformamide (5 mg, 10 mol %). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford the title compound (0.25 g, quantitative).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1>O>[Br:21][C:22]1[CH:23]=[N:24][C:25]([O:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[N:26][CH:27]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(CO)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ncc(Br)cn1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
2,2-Diethoxyethanol (1.6 g) and cesium carbonate (5.8 g) were added to DMF solution (10 mL) of 5-bromo-2-chloropyrimidine (1.15 g), and stirred at room temperature for 12 hours. After addition of water, the reaction liquid was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (C-200; ethyl acetate:hexane=1:9-1:4) to provide the title compound (1.63 g, 94%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[C:11]([C:15]1[CH:16]=[C:17]([C:25](=[O:27])[CH3:26])[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>CN(C)C=O>[Br:7][CH2:8][CH2:9][O:21][C:20]1[C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]([C:25](=[O:27])[CH3:26])=[CH:16][C:15]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: BrCCBr
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])c(OCCBr)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
Potassium carbonate (4.65 g, 33.7 mmol) and 1,2-dibromoethane (31.7 g, 166.6 mmol) were added to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (8.0 g, 33.7 mmol) in dimethylformamide (200 ml) and the mixture was stirred at room temperature for 12 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield 1-[4-(2-bromoethoxy)-3-(tert-butyl)-5-nitrophenyl]-1-ethanone (8.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]2([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=1.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]2([OH:16])[CH2:11][CH2:12][N:13]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][C:32]([F:34])=[CH:31][C:30]=3[F:35])[CH2:14][CH2:15]2)[N:7]=1
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: Nc1nc(C#CC2(O)CCNCC2)cn2nc(-c3ccco3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(C#CC2(O)CCN(Cc3c(F)cc(F)cc3F)CC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a solution of 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-ylethynyl)-piperidin-4-ol (22 mg,0.068 mmol) and 2,4,6-trifluoro-benzaldehyde (11 mg, 0.068 mmol) in CH2Cl2 (2 mL) was added sodium triacetoxyborohydride (32 mg, 0.15 mmol) and acetic acid (6 uL, 0.10 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of silica-gel, washed with ethyl acetate. The eluant was concentrated. The residue was isolated by reversed phased HPLC eluting with a water/acetonitrile gradient to yield 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-ylethynyl)-1-(2,4,6-trifluoro-benzyl)-piperidin-4-ol (1 mg, 3%). 1H NMR (300 MHz, DMSO): δ 7.92 (br s, 1H), 7.70 (m, 3H), 7.41 (s, 2H), 7.14 (s, 1H), 6.72 (s, 1H), 4.43 (s, 2H), 3.80 (m, 4H), 2.12-1.96 (m, 4 H). MS: m/z: 469 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([N:25]([C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:50]([Br:57])=[CH:49][CH:48]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>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>[Br:57][C:50]1[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:47]([C:14]2[CH:13]=[C:12]([N:25]([C:32]3[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=[C:10]([N:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:15]=2)=[CH:48][CH:49]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: Cc1cc(C)cc(N(c2ccccc2)c2cc(B3OC(C)(C)C(C)(C)O3)cc(N(c3ccccc3)c3cc(C)cc(C)c3)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(N(c2ccccc2)c2cc(-c3ccc(Br)c4ccccc34)cc(N(c3ccccc3)c3cc(C)cc(C)c3)c2)c1

Procedure:
13.74 g of a product (yield: 68%) was obtained in the same manner as described in the synthesis method of intermediate 2-3 except that N1,N3-bis(3,5-dimethylphenyl)-N1,N3-diphenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-diamine (17.84 g, 30 mmol), 1,4-dibromonaphthalene (9.44 g, 33 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), K2CO3 (12.44 g, 90 mmol), THF (90 mL), and water (45 mL) were used.
Reaction SMILES: [OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH:8]3[CH2:13][CH:12]([C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][NH:10][CH2:9]3.C(N(C(C)C)CC)(C)C.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C(Cl)Cl>[OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH:8]3[CH2:13][CH:12]([C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][N:10]([C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:39])[CH2:9]3
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CNCC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CC2CN(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To ethyl 3-hydroxy-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,11-methanopyrimido[1,2-a][1,5]diazocine-2-carboxylate (0.26 g, 0.661 mmol) in CH2Cl2 (5 mL) was added diisopropylethylamine (0.576 mL, 3.31 mmol) and benzylchloroformate (0.102 mL, 0.727 mmol). The reaction mixture was stirred at 23° C. for 16 hours. HCl (1N, 15 mL) was then added to the reaction mixture and the organic material extracted with CH2Cl2 (3×15 mL) and ethyl acetate (3×15 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The organic material was purified by Silica gel column chromatography (Biotage flash chromatography system) eluting with gradient of ethyl acetate 100% to ethyl acetate methanol (1:9) to afford 0.036 g (13% yield) of the title compound. 1H NMR (400 MHz, MeOD) δ ppm 7.36 (5 H, s), 4.95-5.10 (2 H, m) 3.95-4.40 (2 H, br m), 2.75-3.30 (5 H, br m), 1.75-2.50 (4 H, m), 0.95-1.45 (4 H, m). LCMS (+ESI, M+H+) m/z: 414.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[CH:8]=2)[CH:3]=[CH:2]1.I[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1/[C:16](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:17](=[O:23])[NH:18]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3/[C:16](=[CH:24]/[C:25]3[NH:26][CH:27]=[CH:28][C:29]=3[O:30][CH3:31])/[C:17](=[O:23])[NH:18]4)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3ccc4cc[nH]c4c3)c21
Temperature: 90 °C
Yield: 61.9 %

Procedure:
A solution of 6-indoleboronic acid (36 mg, 0.22 mmol) (from Step A above), (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one (54 mg, 0.15 mmol) (Starting Material 3) and sodium carbonate (52 mg, 0.49 mmol) in 5 mL DME and 2.5 mL water was degassed for 15 min. by bubbling argon through the solution. Dichlorobis(triphenylphosphine)palladium (II) (10 mol %) (Aldrich) was then added and the reaction was heated at 90° C. for 2 days. The reaction was then poured into 100 mL water and the product was extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting product, (Z)-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one), was purified via flash column chromatography (40% EtOAc/hex) to yield 33 mg (62%) orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[N:21]=[C:20]([F:22])[C:19]([NH2:23])=[CH:18][CH:17]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:20]1[C:19]([NH2:23])=[CH:18][CH:17]=[C:16]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)[N:21]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: Nc1ccc(Br)nc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(N)c(F)n3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
5-Methoxybenzofuran boronic acid (345 mg, 1.80 mmol), 6-bromo-2-fluoro-pyridin-3-ylamine (286.5 mg, 1.50 mmol), Pd(PPh3)2Cl2 (25.2 mg, 0.036 mmol) and Et3N (475.5 μL, 3.41 mmol) were mixed in EtOH (10 mL) in a microwave vial. The reaction mixture was stirred at 140° C. for 10 minutes in a microwave reactor. The volatiles were then removed under reduced pressure and water was added (20 mL). The product was extracted with ethyl acetate (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of the crude product by flash column chromatography using 25% ethyl acetate in hexane gave 2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-ylamine (268 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.58 (d, J=7.6 Hz, 1 H), 7.39 (d, J=9.0 Hz, 1H), 7.15 (m, 1H), 7.14 (s, 1H), 7.04 (d, J=2.6 Hz, 1H), 6.88 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H). ESMS: m/z 259.47 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.C(=O)([O-])O.[Na+]>C(O)CC>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[N:3]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:1]=2)[CH:4]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: Cc1cc(Br)cn2cc(-c3ccc(Cl)cc3)nc12
Temperature: 80 °C
Yield: 58.2 %

Procedure:
1.70 g of 2-amino-5-bromo-3-methylpyridine and 2.13 g of 2-bromo-1-(4-chlorophenyl)ethanone in 75 ml of n-propanol are placed in a round-bottomed flask. 1.08 g of sodium hydrogen carbonate are added. The mixture is heated at 80° C. for 6 h. The reaction mixture is allowed to cool and the solvent is evaporated off under reduced pressure. The residue is taken up between dichloromethane and water, the organic phase is then separated and dried, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. The solid obtained is triturated from diethyl ether and recovered by filtration. 1.7 g of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:34]([CH2:35]OS(C)(=O)=O)=[CH:33][N:32]=[CH:31]1.CN1C(CO)=CN=C1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:34]2[N:30]([CH3:29])[CH:31]=[N:32][CH:33]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cn1cncc1COS(C)(=O)=O
Agent: Cn1cncc1CO
Product: Cn1cncc1Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 3-methyl-3H-imidazol-4-ylmethyl ester (prepared by mesylation of the commercially available (3-methyl-3H-imidazol-4-yl)-methanol) gave the title compound. ES-MS m/e (%): 493.1(M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl.[Cl:9][CH2:10][C:11](=[NH:14])OC>CO>[ClH:9].[O:1]=[C:2]1[NH:3][CH2:4][CH2:5][N:6]([C:11](=[NH:14])[CH2:10][Cl:9])[CH2:7]1
Reactant: COC(=N)CCl
Reactant: O=C1CNCCN1
Agent: Cl
Solvent: CO
Product: N=C(CCl)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 197.1 %

Procedure:
8.64 g of 2-oxopiperazine were added to a solution of 12.4 g of methyl 2-chloroacetimidate hydrochloride in 44.8 ml of anhydrous methanol, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a small amount of insoluble material was filtered off and the solvent was distilled off from the filtrate. Ether was added to the residue, and the precipitated crystals were collected by filtration and washed with ether, giving 18.0 g of 2-(3-oxopiperazin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=2)[C:14](=[O:16])[CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)pyrrolidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.80 min.; [M+H]+: 396.00 g/mol.
Reaction SMILES: [C:1]([N:8]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].C1COCC1>CO>[C:1]([N:8]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccnc1CN(Cc1ccc(C(=O)O)c2ccccc12)C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
The compound obtained in Example 74-2 (1.0526 g) was dissolved in methanol (10 ml), and 1 N aqueous solution of sodium hydroxide (10 ml) and THF (10 ml) were added. The mixture was stirred for 2.5 hours. Part of the solvent was removed by distillation while adding water to the reaction solution. After adjusting the pH to 6, the water layer was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation, and the residue was dried under vacuum to obtain the title compound (0.8551 g) as a pale yellow solid.
Reaction SMILES: C[CH:2](C)[CH:3](C1C=CC=CC=1)[C:4]([NH:6][C@@H:7]1[C@H:14]2[C@H:10]([CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13]2)[CH2:9][CH2:8]1)=O.C(O[C:36]1(O[Si](C)(C)C)[CH2:38][CH2:37]1)C.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:4]1([N:6]([CH:36]2[CH2:37][CH2:38]2)[C@@H:7]2[C@H:14]3[C@H:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[CH2:13]3)[CH2:9][CH2:8]2)[CH2:2][CH2:3]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1cccc(CN2C[C@@H]3CC[C@H](N(C4CC4)C4CC4)[C@@H]3C2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3aS*,4S*,6aR*)-2-(3-(Trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (228 mg, 0.802 mmol) from Example 122 Step E and (1-ethoxycyclopropoxy)trimethylsilane (140 mg, 0.802 mmol) were combined in dichloromethane (1.5 mL) and 5 mL of acetic acid was added. The reaction was stirred at room temperature for 20 minutes, and then PS-cyanoborohydride (343 mg, 0.802 mmol) was added. The reaction was heated to 40° C. overnight. Silica gel chromatography eluting with 1-10% methanol (2 N ammonia)/dichloromethane to gave the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.48 (d, J=7.6, 2H), 7.42 (d, J=7.6, 1H), 3.64 (d, J=13.6, 1H), 3.51 (d, J=13.6, 1H), 2.94-2.82 (m, 3H), 2.80-2.71 (m, 2H), 2.55 (dd, J=5.4, 9.4, 3H), 2.41 (t, J=8.3, 1H), 2.16 (dd, J=4.7, 8.7, 1H), 1.97-1.70 (m, 7H), 1.70-1.59 (m, 3H), 1.40 (dd, J=6.7, 12.6, 1H); MS (ESI+) m/z 365 (M+H)+.
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:8]=[C:7]([CH2:9]Br)[CH:6]=[CH:5][C:4]=1[F:11].II.C[O:15][C:16]([C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=O>C(OCC)C.O1CCCC1>[Br:2][C:3]1[CH:8]=[C:7]([CH2:9][C:16]([C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[O:15])[CH:6]=[CH:5][C:4]=1[F:11]
Reactant: Fc1ccc(CBr)cc1Br
Reactant: COC(=O)c1cccnc1C(=O)OC
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1C(=O)Cc1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of magnesium turnings (880 mg, 37 mmol) and 2-bromo-4-(bromomethyl)-1-fluorobenzene (1.0 g, 3.7 mmol) in anhydrous diethyl ether (15 ml) was treated with a piece of iodine. The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour. The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) at −78° C. The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:14][N:12]1[CH:13]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:3]=[CH:4][C:5]=2[O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]2[CH:18]=[CH:17][NH:16][C:10]=2[C:11]1=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.6 %

Procedure:
To a solution of Example 3 (0.125 g, 0.377 mmol) and triethylamine (0.131 mL, 0.943 mmol) in dichloromethane (3.0 mL) was added dropwise methanesulfonyl chloride (0.064 mL, 0.830 mmol). The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated. The residue was dissolved in a mixture of dioxane (5 mL) and 1M sodium hydroxide (2 mL) and heated for 1 hour at 90° C. The reaction mixture was cooled and diluted with ethyl acetate, brought to pH 7 with 1 M HCl and partitioned. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-4% methanol in dichloromethane) to afford 0.20 g (77%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.02 (s, 3H) 3.48 (s, 3H) 6.23-6.30 (m, 1H) 6.85 (d, J=7.46 Hz, 2H) 6.99 (t, J=7.29 Hz, 1H) 7.04 (d, J=8.82 Hz, 1H) 7.20-7.29 (m, 5H) 7.39 (d, J=2.71 Hz, 1H) 9.72 (s, 1H) 12.01 (s, 1H). MS (ESI+) m/z 410 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:28][C:27]2[C@:22]([CH3:30])([CH2:23][CH2:24][C:25](=[O:29])[CH:26]=2)[C@@H:21]2[C@@H:5]1[C@H:6]1[C@:18]([CH3:31])([CH2:19][CH2:20]2)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)[CH:2]=[CH2:3]>[Rh](Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[CH2:1]([CH:4]1[CH2:28][C:27]2[C@:22]([CH3:30])([CH2:23][CH2:24][C:25](=[O:29])[CH:26]=2)[C@@H:21]2[C@@H:5]1[C@H:6]1[C@:18]([CH3:31])([CH2:19][CH2:20]2)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)[CH2:2][CH3:3]
Reactant: C=CCC1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCC1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12
Reaction time: 2 h

Procedure:
1.0 g. of the 7-allyl-enone 14, 5 ml. EtOAc and 50 mg. triphenylphosphine rhodium chloride (Wilkinson's catalyst) were allowed to stir two hours (under H2 atmosphere). The reaction products were filtered through 25 ml. silica gel, and evaporated to dryness to yield fairly pure title product, 18, as confirmed by proton NMR.