Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]([N+:24]([O-:26])=[O:25])=[C:15]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[N:14]=1>>[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH:11][C:13]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]([N+:24]([O-:26])=[O:25])=[C:15]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[N:14]=2)[CH3:10])=[N:7][CH:8]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]
Agent: Cl
Product: CCOC(=O)c1nc(N[C@@H](C)c2ncc(F)cn2)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 18 using [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15) and ethyl 2-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-5-nitropyrimidine-4-carboxylate (Intermediate 48) as the starting materials. LCMS: 432 [M+1].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(O)cc1)C(=O)OC
Yield: 83.3 %

Procedure:
A suspension of methyl 3-[4-benzyloxyphenyl)-2-ethoxypropanoate (3.7 g, 11.78 mmol; preparation 2) and 10% Pd-C (0.37 g) in ethyl acetate (50 mL) was stirred at 25° C. under 60 psi hydrogen pressure for 24 h. The catalyst was filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) as an eluent to afford the title compound (2.2 g, 84%) as an oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:21]([C:22]([OH:24])=[O:23])=[C:12]2[N:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][N:11]2[N:10]=1.CN(C(O[N:33]1[N:41]=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:21]([C:22]([O:24][N:40]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[N:41]2)=[O:23])=[C:12]2[N:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)O
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)On1nnc2ccccc21
Temperature: 50 °C

Procedure:
Triethylamine (994.9 mg, 1.370 mL, 9.832 mmol) was added to a suspension of 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5d (2.2 g, 8.938 mmol) in chloroform (22 mL). TBTU (2.870 g, 8.938 mmol) was added to the solution and the reaction mixture was heated at 50° C. for 20 min, during which time a yellow precipitate formed. The reaction mixture was cooled to ambient temperature. The precipitate was isolated by filtration and washed with chloroform to leave the product (benzotriazol-1-yl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate) 6d as an off white solid (2.8 g, 86% yield).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.[Br:30][C:31]1[N:36]=[C:35]([CH:37](O)[CH2:38][O:39][CH2:40][CH3:41])[CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:30][C:31]1[N:36]=[C:35]([CH:37]([O:15][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:38][O:39][CH2:40][CH3:41])[CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CCOCC(O)c1cccc(Br)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A solution of diisopropylazodicarboxylate (0.96 mL, 4.89 mmol) in dry THF (35 mL) was added drop-wise, under nitrogen, over 2 h (using a syringe pump) to a solution of ethyl (4-hydroxy-2-methylphenoxy)acetate (735 mg, 3.50 mmol), 1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol (860 mg, 3.49 mmol) and triphenylphosphine (1.28 g, 4.88 mmol) in dry THF (35 mL) at 0° C. The resulting mixture was stirred under nitrogen and gradually allowed to warm to room temperature over 21 h. The solvent was then removed in vacuo and the residue purified by SPE (silica, 2×50 g cartridge), eluting with cyclohexane:EtOAc (gradient 20:1 to 1:1) to afford the title compound as an oil (966 mg).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl[C:36](=[O:47])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:36](=[O:47])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: COC(=O)CCCCCCC(=O)Cl
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCCCCCC(=O)OC)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure J using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and methyl 8-chloro-8-oxooctanoate as a colorless oil (97%). 1H NMR (CDCl3, 300 MHz) δ 7.69 (br s, 1H), 7.44 (m, 4H), 7.18 (m, 4H), 7.04 (m, 1H), 6.92 (d, J=8.7 Hz, 1H), 4.88 (s, 2H), 3.66 (s, 3H). 2.63 (t, J=7.5 Hz, 2H), 2.28 (t, J=7.3 Hz, 2H), 2.05 (t, J=7.3 Hz, 2H), 1.75 (s, 6H), 1.61 (m, 6H), 1.38 (m, 2H), 1.26 (m, 4H), 0.94 (t, J=7.3 Hz, 3H). M+ (ESI): 610.2. HPLC, Rt: 5.81 min (Purity: 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](B(O)O)=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.OO.S(OOS([O-])(=O)=O)([O-])(=O)=[O:18].[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](=[O:18])[CH:7]=[C:8]([CH3:11])[NH:9][CH:10]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: COCOc1cnc(C)cc1B(O)O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c[nH]c(C)cc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 5-(methoxymethoxy)-2-methylpyridin-4-ylboronic acid (500 mg, 2.54 mmol) in tetrahydrofuran (12.7 mL), an aqueous solution of hydrogen peroxide (purity 30%) (2.9 mL, 25.4 mmol) was added at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction solution was added a saturated aqueous solution of sodium persulfate, and concentrated in vacuo. The obtained residue was washed and filtered with chloroform/methanol, and the title compound (440 mg (yield >100%)) was obtained as a yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH3:21])[CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2>C(O)(=O)C.Cl>[Cl:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH3:21])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOC(=O)c1cn(C)c2nc3cc(Cl)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reaction time: 4 h
Yield: 92.4 %

Procedure:
A suspension of 15 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 150 cm3 of acetic acid and 50 cm3 of hydrochloric acid as a 17.5% aqueous solution is heated at a temperature close to 100° C., with stirring, for 4 hours. After cooling to a temperature close to 20° C., the product is drained and washed with twice 150 cm3 of ethanol and then twice 100 cm3 of diethyl ether. 12.7 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a beige solid which sublimes at 400°-405° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:28][CH3:27])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CN
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CNC)cc2C)ncn1
Reaction time: 24 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with methylamine (0.25 ml, 2M in THF; 0.5 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours a further portion of methylamine (1 ml, 2M in THF; 2 mmol) was added. After stirring for a further 24 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](O)=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C.CC1(C)[O:41][CH:40]([CH2:42][NH:43][CH2:44][CH2:45][CH3:46])[CH2:39][O:38]1>>[NH2:8][C:9]1[CH2:10][C:11]([C:33]([N:43]([CH2:42][CH:40]([OH:41])[CH2:39][OH:38])[CH2:44][CH2:45][CH3:46])=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:27])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCNCC1COC(C)(C)O1
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Product: CCCN(CC(O)CO)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedures as described in Example 101 (Step H and I) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propan-1-amine.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2].CCN(CC)CC.C1COCC1.[SH2:27]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[S:27])[NH2:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2]
Reactant: S
Reactant: CC(=O)n1ncc2cc(C#N)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)n1ncc2cc(C(N)=S)ccc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 1-acetyl-1H-indazole-5-carbonitrile (1.1 g, 6 mmol), Et3N (2.5 mL, 17.8 mmol) and THF (20 mL) was bubbled in H2S gas over 10 min. Stirred at 0° C. for 24 h. Concentrated in vacuo to give a yellow solid which was triturated with CH2Cl2 and filtered insoluble solid to give 1-acetyl-1H-indazole-5-carbothioic acid amide as a yellow solid. MS m/z: 220.0 (M+H). Calc'd for CloH9N3OS 219.26.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[H][H]>C(O)C.[Ni]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: c1cnc2[nH]ccc2c1
Agent: [Ni]
Solvent: CCO
Product: c1cnc2c(c1)CCN2
Yield: 59.6 %

Procedure:
A solution of 7-azaindole (20.0 g, 169 mmol) in ethanol (200 ml) was treated with wet Raney Nickel (4 g, 50% water) and stirred in a hydrogen atmosphere at 5 atmospheres pressure at 95° C. over 2 days. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate followed by increasingly polar mixtures of methylene chloride and methanol (saturated with ammonia) to give 7-azaindoline (12.1 g, 79%).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[CH2:1]([O:11][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCCCCCCCCO
Product: C=CCCCCCCCCOC(=O)OCc1ccccc1

Procedure:
Starting Material: dec-9-en-1-ol and benzyl chloroformate.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[C:5]=1[OH:11])([O-:3])=[O:2].[F-].[Cs+].Br[CH:15](Br)[CH3:16]>CN(C=O)C>[N+:1]([C:4]1[C:5]2[O:11][CH2:16][CH2:15][O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Reactant: CC(Br)Br
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1OCCO2
Temperature: 110 °C
Yield: 20.8 %

Procedure:
To a solution of compound 8A (3.0 g, 19.4 mmol) in DMF (40 mL) was added CsF (14.7 g, 96.8 mmol), followed by dibromoethane (1.84 mL, 21.3 mmol). The mixture was heated to 110° C. for 1.5 h, then cooled to rt, partitioned between water and Et2O. The separated Et2O layer was washed with water, saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 5% MeOH in CH2Cl2 to afford the title compound (0.73 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]([CH3:24])[CH:26]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cn(C)c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-methyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=489.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](Cl)=[N:8][OH:9])=[N:4][O:5][N:6]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:8][OH:9])[NH:15][CH2:14][CH2:13][O:12][CH3:11])=[N:4][O:5][N:6]=1
Reactant: COCCN
Reactant: Nc1nonc1C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCNC(=NO)c1nonc1N
Temperature: 2.5 °C
Yield: 118.8 %

Procedure:
4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (200.0 g, 1.23 mol) was mixed with ethyl acetate (1.2 L). At 0-5° C. 2-methoxyethylamine [Aldrich, product #143693] (119.0 mL, 1.35 mol) was added in one portion while stirring. The reaction temperature rose to 41° C. The reaction was cooled to 0-5° C. Triethylamine (258 mL, 1.84 mol) was added. After stirring 5 min, LCMS indicated reaction completion. The reaction solution was washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated to give the desired product (294 g, 119%) as a crude dark oil. LCMS for C6H12N5O3 (M+H)+: m/z=202.3. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 6.27 (s, 2H), 6.10 (t, J=6.5 Hz, 1H), 3.50 (m, 2H), 3.35 (d, J=5.8 Hz, 2H), 3.08 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH2:13]([OH:18])[CH2:14][CH2:15][CH2:16][OH:17]>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:18])=[O:3]
Reactant: OCCCCO
Reactant: COc1ccccc1OC(=O)Cl
Product: COc1ccccc1OC(=O)OCCCCO

Procedure:
The reaction of 2-methoxyphenyl chloroformate with 1,4-butanediol is conducted on a 0.01 scale employing the same conditions as described in Example IV. A 1.5 g yield of the pure product is obtained as an oil.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25](=[O:40])[CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][N:10]=2)[CH2:7][CH2:6][CH:5]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25](=[O:40])[CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)[CH2:21]2)[CH2:4][CH2:3]1
Reactant: CNC(=O)c1ccc(C2(O)CCC(=O)CC2)nc1
Reactant: N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1ccc(C2(O)CCC(N[C@H]3CCN(C(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.9 %

Procedure:
6-(1-Hydroxy-4-oxocyclohexyl)-N-methylnicotinamide (100 mg, 0.4 mmol) and 126 mg (0.4 mmol) of N-{2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide were dissolved in 10.0 mL of methylene chloride. To the solution was added 170 mg (0.8 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 h. Direct chromatography on silica gel gave 48 mg (23%) of the final desired product (top spot on TLC and first peak on HPLC). MS: (M+H)+ 547.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])([OH:3])=[O:2].[CH3:17]O.S(=O)(=O)(O)O>O>[CH3:17][O:2][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])=[O:3]
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of 1.0 g (4,5 mmol) 1-carboxymethylquinoxaline-2,3(1H,4H)-dione, 15 ml dry methanol and 0,2 ml concentrated sulfuric acid was stirred at 80° C. for 1 h. After cooling to 25° C. the reaction mixture was poured in water and made alkaline. The precipitate was filtered off and recrystallized (acetone) to give 0.22 g (21%) 1-methoxycarbonylmethylquinoxaline-2,3(1H,4H)-dione. M.p. 269° C. 1H-NMR (DMSO-d6 ): 12.0 (1H, broad s), 7.1 (4H, s), 4.9 (2H, s), 3.7 (3H, s).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].[O:19]=[S:20]1(=[O:33])[CH2:25][CH2:24][CH:23]([C:26]2[C:27](F)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:27]2[C:26]([CH:23]3[CH2:24][CH2:25][S:20](=[O:33])(=[O:19])[CH2:21][CH2:22]3)=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: O=S1(=O)CCC(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2ncccc2C2CCS(=O)(=O)CC2)cc1)c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.485 g, 2.035 mmol), 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-fluoropyridine (0.311 g, 1.356 mmol), and cesium carbonate (1.326 g, 4.07 mmol) in NMP (5 mL) in a sealed tube was heated at 200° C. in 2 h. The reaction mixture was cooled, taken in H2O, filtered the dark brown solid, purified by ISCO (50% EtOAc/Hexanes) to give the expected product as a tan solid. MS (ESI, pos. ion) m/z: 448.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH:6]([O:12][CH3:13])[CH2:5]2.[C:14]([S@:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[N:20]\[S@@:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19])/[C@@H:6]([O:12][CH3:13])[CH2:5]2
Reactant: COC1Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Product: CO[C@H]1Cc2cc(Cl)ccc2/C1=N\[S@](=O)C(C)(C)C
Temperature: 68 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
A 22 L multi-neck reactor equipped with a condenser, a nitrogen inlet, a heating mantle and an overhead mechanical stirrer was charged with 5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-one (18) (622.88 g, 3.17 mol) and (R)-tert-butylsulfinamide (460.7 g, 3.8 mol). Tetrahydrofuran (3100 mL) was added to the mixture and the temperature dropped to 9° C. Ti(OEt)4 (985 mL, 4.76 mol) was added over 10 minutes. The mixture was heated to 68° C. and all solids dissolved at about 35° C. After 5 hours, the reaction achieved a 50% yield as determined by HPLC wt % assay. The reaction was stirred at 68° C. for an additional 5 hours until the undesired diastereomer decomposed to less than 5% (AUC). The reaction was cooled to ambient temperature over 2 hours and stirred for 16 hours. HPLC analysis indicated no obvious change in reaction profile during this period. This crude reaction mixture was taken in to the next step without further purification.
Reaction SMILES: [C:1]1([C@H:7]([NH:38][C:39]([O:41][C@@H:42]2[CH:47]3[CH2:48][CH2:49][N:44]([CH2:45][CH2:46]3)[CH2:43]2)=[O:40])[C:8]2[CH:9]=[C:10]([CH:35]=[CH:36][CH:37]=2)[O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=2)[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27](OC)[O:28]C)=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(=O)([O-])O.[Na+]>[C:1]1([C@H:7]([NH:38][C:39]([O:41][C@@H:42]2[CH:47]3[CH2:48][CH2:49][N:44]([CH2:45][CH2:46]3)[CH2:43]2)=[O:40])[C:8]2[CH:9]=[C:10]([CH:35]=[CH:36][CH:37]=2)[O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=2)[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]=[O:28])=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(Cc1ccc(COC(=O)c2cccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)c2)cc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=CCc1ccc(COC(=O)c2cccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(2,2-dimethoxyethyl)benzyl 3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (0.100 g, 0.15 mmol) in acetone (5 mL) was added para-toluenesulfonic acid monohydrate (0.086 g, 0.45 mmol) and the mixture stirred at RT for 1 hour. The reaction mixture was diluted with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used in the next step with no further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]=[C:13]([S:22][CH3:23])[N:12]=1.C[C:25]1[CH:30]=[CH:29][C:28]([N:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH2:32])=[CH:27][CH:26]=1>O1CCOCC1>[CH3:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([S:22][CH3:23])[NH:12][C:11]2=[N:32][N:31]([C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)N(N)c1ccc(C)cc1
Reactant: CSc1nc(Cl)c2cc(C)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)N(N=c1[nH]c(SC)nc2ccc(C)cc12)c1ccccc1

Procedure:
N,N-Diisopropylethylamine (0.104 mL, 0.6 mmol) was added to a solution of 11b (0.071 g, 0.3 mmol) and 10a, (0.057 g, 0.3 mmol) in 5 mL of dioxane and the solution was heated at reflux for 48 h; during which a white precipitate fell out. The white slurry was filtered and the precipitate was washed with dioxane to give 12 as a white solid. (0.110 g, 100%). mp. 229.7° C.;