Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:30])[CH3:29])[C@@H:23]([CH3:31])[CH2:22][NH:21]4)[CH:15]=[N:14]2)[CH2:12][CH2:11]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>ClCCCl>[CH:32]1([C:35]([N:21]2[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([C:16]4[CH:15]=[N:14][N:13]([CH:10]5[CH2:12][CH2:11]5)[CH:17]=4)[CH:19]=3)[N:24]([C:28](=[O:30])[CH3:29])[C@@H:23]([CH3:31])[CH2:22]2)=[O:36])[CH2:34][CH2:33]1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2NC[C@@H]1C
Reactant: O=C(Cl)C1CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(C(=O)C2CC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
N,N-Diisopropylethylamine (0.120 mL, 0.688 mmol) was added to a solution of (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.068 g, 0.229 mmol) and cyclopropanecarbonyl chloride (0.031 mL, 0.344 mmol) in 1,2-dichloroethane (2.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(4-(cyclopropanecarbonyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.060 g, 72%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.68-0.77 (m, 1 H), 0.83-1.02 (m, 5 H), 1.02-1.08 (m, 5 H), 1.87-2.04 (m, 1 H), 2.12 (s, 3 H), 3.33 (m, 1 H), 3.74 (tt, J=7.33, 3.81 Hz, 1 H), 4.61 (m, 1 H), 4.69-4.86 (m, 1 H), 7.37-7.57 (m, 2 H), 7.65 (s, 1 H), 7.85 (s, 1 H), 8.25 (s, 1 H). MS (ESI, pos. ion) m/z 365. [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.[H-].[Na+].[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])=[CH:3][N:2]=1
Reactant: Nc1ccnnc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of Pyridazin-4-ylamine (30 mg, 0.31 mmol, [Cas. No. 20744-39-2]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (15 mg, 16%)
Reaction SMILES: [CH2:1]([O:3][NH:4][CH:5]([CH3:16])[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15])[CH3:2].C(N(CC)CC)C.[F:24][CH:25]([F:35])[C:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]([CH3:34])[N:27]=1>ClCCl.O>[CH2:1]([O:3][N:4]([CH:5]([CH3:16])[CH2:6][C:7]1[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=1[Cl:13])[C:31]([C:30]1[C:26]([CH:25]([F:35])[F:24])=[N:27][N:28]([CH3:34])[CH:29]=1)=[O:32])[CH3:2]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CCONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
To a solution of O-ethyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (0.5 g, 1.63 mmoles) in dichloromethane (5 ml) was added triethylamine (0.566 ml, 4.07 mmloes) followed by drop wise addition of a solution 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.34 g, 1.79 mmol) in dichloromethane at a temperature of 0° C. After the complete addition of acid chloride the mixture was stirred for 18 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer were washed with 2N HCl, followed by saturated NaHCO3, then water and finally brine, dried over sodium sulfate and evaporated off solvent under reduced pressure. Resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (0.390 g, 50%) as off white solid. m.p: 111-114° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:26]([N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reaction time: 3 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (1 g, 2.4 mmol) in 24 mL of CH2Cl2 was added 4-dimethylamino pyridine (0.88 g, 7.2 mmol) and acetyl chloride (0.21 g, 2.6 mmol). The solution was stirred for 3 h and the solvent was removed under reduced pressure. The residue was treated with saturated NH4OH (20 mL) and the suspension was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (1×50 mL)), dried over MgSO4, filtered and concentrated to leave a solid. The solid was triturated with ether and was filtered to leave the title compound: MS (M+H): 381 (base peak).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.C(OCC)(=O)C>[CH2:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:2][CH2:3]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(N3CCNCC3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOc2nc(N3CCN(Cc4ccccc4)CC3)ccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a mixture of the compound (0.28 g) obtained in Example 33, step 1, potassium carbonate (0.23 g) and DMF (5 mL) was added benzyl bromide (109 μL), and the mixture was stirred at room temperature for 18 hr. Ethyl acetate and water were added to the reaction mixture. The organic layer was washed with water and brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→30% ethyl acetate/hexane) to give tert-butyl 8-(4-benzylpiperazin-1-yl)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.24 g, 68%) as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]1[C:11]([NH2:13])=[O:12].C(Cl)(=O)[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[NH:1]1[C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]=2[C:11](=[O:12])[NH:13][C:15]1=[O:16]
Reactant: NC(=O)C1Oc2ccccc2C1N
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=O)c2oc3ccccc3c2[nH]1
Temperature: 115 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a stirred solution of 3-amino-2,3-dihydrobenzofuran-2-carboxamide (82.2 mg, 0.461 mmol, 1.0 eq.) in anhydrous toluene (8 mL) under an inert atmosphere was added oxalyl chloride (70.2 mg, 553 μmol, 1.2 eq.) in a dropwise manner. The resulting mixture was heated to reflux (115° C.) for 4 hours whereupon it was cooled and stirred for a further 16 hours. The crude reaction mixture was concentrated to half of its volume and filtered to give a colorless solid (41.5 mg, 45%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:12]=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1)[CH:12]=[O:13]
Reactant: COC(=O)C(=O)c1ccc(N(C=O)CCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=CN(CCOc1ccc2ccccc2c1)c1ccc(C(=O)C(=O)O)cc1
Yield: 66.5 %

Procedure:
A solution of 4-[N-[2-(2-naphthalenyloxy)ethyl]formamido]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (2 mL) and the mixture was concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated. The residue was crystallized acetone-hexane to give 0.32 g of 4-[N-[2-(2-naphthalenyloxy)ethyl]formamido]-alpha-oxobenzeneacetic acid, mp 155°-156° C. as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]([CH2:18][CH2:19][C:20]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:21]([NH:23][O:24]C3CCCCO3)=[O:22])[C:14](=[O:36])[CH:13]=2)=[CH:8][CH:7]=1.Cl>O1CCOCC1.CO>[OH:24][NH:23][C:21](=[O:22])[C:20]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:19][CH2:18][N:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:7][CH:8]=2)=[CH:13][C:14]1=[O:36]
Reactant: CC(CCn1ccc(-c2ccc(OCCCO)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(CCn1ccc(-c2ccc(OCCCO)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
To 4-(4-(4-(3-hydroxypropoxy)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (120 mg, 0.230 mmol) was added 4 N hydrogen chloride in dioxane (5.0 mL) and methanol (0.50 mL). The reaction was stirred for 30 minutes and then evaporated in vacuo onto silica gel. Chromatography on silica gel with a dichloromethane-methanol gradient (1%-25%) gave the title compound as a white foam (20.8 mg, 20.1%). 1H NMR: 400 MHz, (CD3OD) δ ppm 1.71 (s, 3H), 2.06 (m, 2H), 2.38 (ddd, J=13.2, 10.8, 4.8 Hz, 1H), 2.53-2.62 (m, 1H), 3.11 (s, 3H), 3.76 (t, J=6.2 Hz, 2H), 3.88-3.96 (m, 1H), 4.14 (t, J=6.3 Hz, 2H), 4.29 (ddd, J=12.5, 10.8, 4.9 Hz, 1H), 6.75 (m, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.62-7.69 (m, 3H). LCMS: 437.2 (M−1).
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:44])[NH:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:43]=[CH:42][C:22]3[N:23]=[C:24]([O:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]5[N:38]=[CH:37][C:36]([CH2:39][CH2:40][CH3:41])=[CH:35][N:34]=5)[CH2:29][CH2:28]4)[S:25][C:21]=3[CH:20]=2)=[CH:15][CH2:14]1)(=[O:12])=[O:11])(=O)C.[Li+].[OH-]>C1COCC1>[OH:4][CH2:5][C:6]([NH:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:43]=[CH:42][C:22]3[N:23]=[C:24]([O:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]5[N:34]=[CH:35][C:36]([CH2:39][CH2:40][CH3:41])=[CH:37][N:38]=5)[CH2:31][CH2:32]4)[S:25][C:21]=3[CH:20]=2)=[CH:15][CH2:14]1)(=[O:11])=[O:12])=[O:44]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCNC(=O)COC(C)=O)CC5)cc4s3)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCNC(=O)CO)CC5)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 2-oxo-2-(2-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)ethylamino)ethyl acetate (32 mg, 0.05 mmol) in THF (1 mL) was added LiOH (saturated, aqueous, 0.5 mL). The mixture was stirred at rt overnight. It was extracted with DCM (3×2 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated to afford the desired product as a white solid (28 mg, 95% purity, 89% yield). 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 2H), 7.63 (m, 2H), 7.38 (m, 1H), 6.06 (m, 1H), 5.43 (m, 1H), 3.75 (m, 12H), 2.88-0.72 (m, 17H). LCMS (m/z)=601 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[C:11](=[O:16])[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:11](=[O:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)N(Cc1ccc(C(C)(C)C)cc1)c1ccc(-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(N(Cc3ccc(C(C)(C)C)cc3)C(=O)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A mixture of methyl N-[4-(tert-butyl)benzyl]-N-(4′-methoxybiphenyl-4-yl)oxamate (230 mg, 0.533 mmol), methanol (1.5 ml), 2N aqueous sodium hydroxide (0.8 ml) and tetrahydrofuran (1.5 ml) was stirred at room temperature for 10 minutes. The reaction mixture was adjusted to pH 5-6 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (160 mg, 71.9%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([CH:20]=1)[NH:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]2[N:13]=[C:14]([S:16][CH3:17])[S:15][C:11]=2[CH:10]=1.BrC1C(OC)=CC(NCC2C=CC3N=C(SC)SC=3C=2)=C([N+]([O-])=O)C=1>>[Br:1][C:2]1[CH:20]=[C:6]([NH:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[S:15][C:11]=3[CH:10]=2)[C:5]([NH2:21])=[CH:4][CH:3]=1
Reactant: CSc1nc2ccc(CNc3cc(Br)ccc3[N+](=O)[O-])cc2s1
Agent: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Product: CSc1nc2ccc(CNc3cc(Br)ccc3N)cc2s1

Procedure:
5-Bromo-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine was synthesized as a brown solid (920 mg) using a procedure analogous to that described in Step 2 of Example 41, substituting 5-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline from the previous step for 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline used in Example 41. LCMS (ESI) m/z 379, 381 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:5]=2[C:4](=[O:16])[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>ClCCl>[CH3:17][C:2]1([CH3:1])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13]([N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[O:15])[C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(CCC(=O)O)c[nH]c2C1
Reactant: CCNCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCN(CC)C(=O)CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a suspension of 1.18 g of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5 mmol) in dichloromethane (25 mL) was added 0.97 g (6 mmol) of carbonyldiimidazole. After stirring at room temperature for 2 hours, 2.1 mL (20 mmol) of diethylamine was added. The mixture was stirred at room temperature overnight. The reaction was concentrated and the residue dissolved in dichloromethane, washed with brine, dried and concentrated to give 1.2 g (83% yield) of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-N,N-diethyl-propionamide as a white solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.91 (br s, 1H, NH), 6.46 (s, 1H), 3.20–3.29 (m, 4H, 2×CH2), 2.72–2.76 (m, 2H, CH2), 2.57 (s, 2H, CH2), 2.45 (m, 2H, CH2), 2.17 (s, 2H, CH2), 0.96–1.06 (m, 12H, 4×CH3). MS m/z 290 [M+].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[ClH:10].[Cl:11]N1C(=O)CCC1=O>C(OCC)C.C(O)(=O)C>[ClH:11].[Cl:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CCl)c1cccnc1
Yield: 95 %

Procedure:
To a solution of 3-acetylpyridine (100 g, 0.83 moles) in diethyl ether (1 L) was added of 1 N hydrogen chloride in ether (950 mL) with rapid stirring. The precipitated solids were filtered, washed with ether and dried. The hydrochloride salt (129 g, 0.83 mol) was added to a 5 L reactor equipped with a mechanical stirrer and dissolved with 1 N HCl in acetic acid (830 mL). The mixture was stirred until a clear solution was obtained, then N-chlorosuccinimide (111 g, 0.83 mol) was added, resulting in a yellow mixture. The solution was stirred at room temperature for 18 hours, gradually becoming a colorless suspension. The solids were collected by filtration and washed with ether; the filtrate was treated overnight with N-chlorosuccinimide (80 g, 0.6 mole) and additional product was collected to yield a white solid (152 g, 95%). 1H-NMR (300 MHz, DMSO-d6) δ10.3 (br s, 1H), 9.27 (s, 1H), 8.96 (d, 1H, J=5.1 Hz), 8.62 (d, 1H, J=9.9 Hz), 7.89 (m, 1H), 5.30 (s, 2H); MS (EI) m/z 155 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:15][CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:17]1([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:15][CH3:16])[CH2:13][CH2:12][CH:11]([CH:18]3[CH2:19][NH:20][CH2:21][CH2:22][N:17]3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: COC1(c2ccc(F)cc2)CCC(=O)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: COC1(c2ccc(F)cc2)CCC(C2CNCCN2C(=O)OCc2ccccc2)CC1
Yield: 35.7 %

Procedure:
A mixture of 4-(4-fluorophenyl)-4-methoxycyclohexanone (2,2 g, 10 mmole), phenylmethyl 1-piperazinecarboxylate (2.2 g, 10 mmole), titanium(IV) isopropoxide (3.7 ml, 11 mmole) were mixed, reacted and reduced with sodium borohydride (0.4 g, 10 mmole) as in example 5. The crude product was purified by chromatography on silica eluting with methanol-methylene chloride (1:50) to give phenylmethyl [4-(4-fluorophenyl)-4-methoxy-1-cyclohexyl]-1-piperazinecarboxylate (35.7%, mp: 68°-69° C.).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CON(C)[C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][CH3:26])[CH:19]=1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:26][O:25][CH2:24][C:20]1[CH:19]=[C:18]([CH2:17][C:16](=[O:27])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:23]=[CH:22][CH:21]=1
Reactant: COP(C)(=O)OC
Reactant: COCc1cccc(CC(=O)N(C)OC)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1cccc(CC(=O)CP(=O)(OC)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Under an atmosphere of argon gas, a solution of dimethyl methylphosphonate (DMMP; 147 g) in anhydrous toluene (1500 ml) was cooled to −74° C. Thereto, n-butyllithium (714 ml; 1.52 M in hexane) was added for 1 hour. The mixture was stirred for 1 hour. Thereto, a solution of N-methoxy-N-methyl-(3-methoxymethylphenyl)acetic acid amide (200 g; prepared in Reference Example 20) in anhydrous toluene (400 ml) was added for 30 minutes. In addition, the mixture was stirred for 2 hours. Thereto, acetic acid (73.5 ml) was added. The mixture was heated to room temperature and poured into water. The organic layer was separated. The organic layer was washed by water and an aqueous saturated solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain the title compound (206.5 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6](=[O:31])[CH2:7][NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20]>C1COCC1>[C:1]([N:8]([CH2:7][C:6]([NH2:5])=[O:31])[C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: C1CCOC1
Product: CC(=O)N(CC(N)=O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
Acetyl chloride (17 μL, 0.24 mmol) was added to a solution of N-{(1R,2R)-1-[(2-amino-2-oxoethyl)amino]-2,3-dihydro-1H-inden-2-yl}-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 28, 100 mg, 0.24 mmol) in THF (10 mL). The reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:2) to afford the title compound (50 mg, 45%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7](/[C:10](/[CH3:16])=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H].CCCCCC.C(OCC)(=O)C>CO.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]([CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1ncc(/C(C)=C/C(=O)OC)n1Cc1ccccc1Cl
Agent: O=[Pt]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1ncc(C(C)CC(=O)OC)n1Cc1ccccc1Cl

Procedure:
A mixture of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-methyl-2-propenoate (165 rag, 0.476 mmol) in methanol (10 mL) and platinum oxide (20 mg) was shaken under one atmosphere of hydrogen for 3 hours. TLC on silica gel with 6:4 hexane/ethyl acetate showed a homogenous spot with an Rf 0.54. The catalyst was filtered, and the filtrate was concentrated to 154 mg (93%) of the title compound.