Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1.C(N(CC)CC)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])[CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCN(S(=O)(=O)c3ccccc3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To 2-Chloro-7-methyl-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (100 mg) in anhydrous DCM (2 ml) and triethylamine (1.5 equiv., 60 μl) at 0° C. was added benzenesulfonyl chloride (1.3 equiv., 45.5 μl) and the reaction mixture was allowed to warm up to room temperature overnight. Chloroform/brine extraction and purification on silica gave 2-chloro-6-(4-benzenesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (104 mg).
Reaction SMILES: Cl.[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:31])([F:30])[F:29])=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:4])[CH3:3].[C:38](=[O:41])([O-:40])[O-:39].[K+].[K+].CN(C=O)C>O>[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:6][C:8]2[O:41][C:38](=[O:40])[O:39][C:27]=2[CH3:12])[CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:30])([F:29])[F:31])=[CH:10][C:11]2[O:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(Cc4oc(=O)oc4C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.5 %

Procedure:
To N-isopropyl-2,2-dimethyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionylamino)-ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride (1.0 g) were added the compound of Reference Example 8 (344 mg), potassium carbonate (45 mg) and DMF (30 ml), and the mixture was stirred at room temperature overnight. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=1:2) to give the title compound (300 mg) as white amorphous.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[Cl:28][C:23]1[CH:22]=[C:21]([C:12]([NH:11][CH:1]=[O:2])([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: O=CO
Reactant: C=CCC(N)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: C=CCC(NC=O)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under cooling on ice, formic acid (140 mL) was added to acetic anhydride (255 mL), followed by stirring at 50° C. for 30 minutes. The reaction mixture was cooled with ice. Subsequently, ethyl 2-amino-2-(3,4-dichlorophenyl)-4-pentenoate (298 g) in tetrahydrofuran (1.5 L) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was neutaralized with saturated aqueous sodium bicarbonate. The resultant mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby give the title compound (334 g). The title compound was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36]([N:39]1[CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]1)([CH3:38])[CH3:37]>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:42]3[CH2:43][CH2:44][N:39]([CH:36]([CH3:38])[CH3:37])[CH2:40][CH2:41]3)[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(O)ccc2n1
Reactant: CC(C)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2cc(OC3CCN(C(C)C)CC3)ccc2n1
Temperature: 35 °C

Procedure:
A mixture of 1 g (0.0046 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 2.4 g (0.0092 mol) of triphenylphospine (Fluka), 2.4 g (0.0092 mol) of 1-isopropyl-piperidin-4-ol and 1.6 ml (0.0092 mol) of di-tert.-butyl azadicarboxylate 40% in toluene in 100 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH 98/2. The product fractions were evaporated and the residue was triturated with diethyl ether to yield after drying under vacuum 1.3 mg (83%) of the title compound as white solid. MS (m/e): 343.3 (M+H)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[O:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1
Reactant: Cc1ncc(Br)n1C
Reactant: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.90 mL, 2.2 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (408.9 mg, 2.336 mmol) in dry THF (12 mL) in a dry ice-acetone bath. After 1-2 minutes, (4-chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.505 g, 1.16 mmol, Intermediate 48: step b) in dry THF (12 mL) was added to the mixture via syringe. After 5 minutes, the reaction was removed from the cold bath and was allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the aqueous mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM). Due to remaining impurities, the material was dissolved in ethyl acetate and washed several times with minimal water. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness. The material was purified by reverse phase chromatography (acetonitrile/H2O+0.05% TFA), basified with saturated aqueous sodium bicarbonate, and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=2.2 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28-7.24 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.96-6.89 (m, 3H), 6.00 (s, 1H), 4.23 (s, 2H), 4.07 (s, 3H), 3.36 (s, 3H), 2.51 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H); MS m/e 531.2 [M+H]+.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CS(C)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][OH:30]>C(Cl)Cl>[N:1]1([C:10]2[N:18]=[C:17]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH2:29][OH:30])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OC[C@@H]1CCCN1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Solvent: ClCCl
Product: OC[C@@H]1CCCN1c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 110 °C
Yield: 64.6 %

Procedure:
250 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 470 mg of (S)-(+)-2-pyrrolidinemethanol. The mixture is then heated at 110° C. for approximately 16 hours. The mixture is allowed to return to ambient temperature. A paste is formed in CH2Cl2 (methylene chloride). Drying is carried out under vacuum. 200 mg of expected product are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:33][CH3:34])=[C:17]3[N:22]([CH:23]=2)[CH:21]=[CH:20][CH:19]=[C:18]3[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([C:41]([O:43][CH3:44])=[O:42])#[C:36][C:37]([O:39][CH3:40])=[O:38]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3=[C:35]([C:41]([O:43][CH3:44])=[O:42])[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:21]4[CH:20]=[CH:19][C:18]([CH2:24][O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])=[C:17]([N:22]34)[C:16]=2[CH2:33][CH3:34])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO[Si](C)(C)C(C)(C)C)c12
Reactant: COC(=O)C#CC(=O)OC
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)OC)c(C(=O)OC)c3ccc(CO[Si](C)(C)C(C)(C)C)c1n32

Procedure:
2-(4-Benzyloxyphenyl)-8-(tert-butyldimethylsilanyloxymethyl)-1-ethylindolizine, prepared in example 81, step 5, was reacted with dimethyl acetylene dicarboxylate by the general synthetic principle outlined in example 23, step 6, to afford dimethyl 3-(4-benzyloxyphenyl)-5-(tert-butyldimethylsilanyloxymethyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate, which was hydrolysed and desilylated by the general synthetic principle outlined in example 23, step 7, to afford 3-(4-benzyloxyphenyl)-4-ethyl-5-hydroxymethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid as yellow crystals in 70% yield. 1H--NMR (DMSO-d6, 200 MHz) δ: 1.32 (t, 3 H); 3.09 (q, 2 H); 5.18 (s, 2 H); 5.19 (s, 2 H); 7.19 (d, 2 H); 7.31-7.58 (m, 7 H); 8.08 (d, 1 H); 8.40 (d, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:32][C:33]2[CH:41]=[C:40]3[C:36]([C:37]([C:42](=[O:44])[CH3:43])=[CH:38][NH:39]3)=[CH:35][CH:34]=2)[CH2:11][C:12]([N:14]2[CH2:18][C@H:17]([F:19])[CH2:16][C@H:15]2[C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.O>[C:42]([C:37]1[C:36]2[C:40](=[CH:41][C:33]([O:32][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:45])=[O:2])=[CH:9][CH:8]=3)[CH2:11][C:12]([N:14]3[CH2:18][C@H:17]([F:19])[CH2:16][C@H:15]3[C:20](=[O:31])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])=[O:13])=[CH:34][CH:35]=2)[NH:39][CH:38]=1)(=[O:44])[CH3:43]
Reactant: COC(=O)c1ccc(C(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)Oc2ccc3c(C(C)=O)c[nH]c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1c[nH]c2cc(OC(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c3ccc(C(=O)O)cc3)ccc12

Procedure:
The title compound was prepared in a similar manner as described for Example 595 from 4-(3-acetyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yloxymethyl)-benzoic acid methyl ester (37.0 mg, 0.058 mmol) and 1N NaOH (0.928 mL, 0.928 mmol) in THF (5 mL) and water (0.5 mL). Solid. MS (LC/MS): 624/626 [M+H]+; tR (HPLC conditions k): 3.48 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5C(OCC5C=CC=CC=5)=O)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[N:22][CH:23]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[N:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[N:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OCc5ccccc5)[nH]4)cc3)nc2)[nH]1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)nc2)[nH]1
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A solution of (S)-2-[5-(2-{4-[2-((S)-1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (317.1 mg, 0.48 mmol) in MeOH (1 mL) was added to a stirred suspension of 10% palladium on carbon (60 mg) and K2CO3 (70 mg) in a solution of MeOH (5 mL) and H2O (0.1 mL) at room temperature under N2. The flask was charged and evacuated three times with H2 and stirred for 3 h at atmosphere pressure. Additional catalyst (20 mg) was then added and the reaction mixture was stirred further for 3 h before it was suction-filtered through diatomaceous earth (Celite®) and concentrated. The residue was diluted with MeOH, filtered through a PVDF syringe filter (13 mm×0.45 μm), distributed into 4 pHPLC vials and chromatographed (gradient elution from 20% B to 100% B over 10 min on a Phenomenex-Gemini C18 column (30×100 mm, 10 μm) where A=95% water, 5% acetonitrile, 10 mM NH4OAc, B=10% water, 90% acetonitrile, 10 mM NH4OAc). After concentration of the selected test tubes by speed vacuum evaporation, there was isolated the title compound as a yellow solid (142.5 mg, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C(C)=CC=CC=1C.O([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Oc1cc(Cl)cc(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](Oc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a solution of 3,5-dichloro-phenol (5.9 g, 36 mmol) in methylene chloride (50 mL) was added 2,6-lutidine (8.38 mL, 72.4 mmol) and triisopropylsilyl triflate (9.7 mL, 36 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 4 h. The reaction was quenched with 0.1 N HCl and diluted with ethyl acetate. The organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with flash chromatography (5% ethyl acetate/hexanes) to give the desired product as a colorless oil (10.5 g, 91%). 1H NMR (400 MHz, CDCl3): δ 6.95 (t, J=1.8 Hz, 1H), 6.76 (d, J=1.8 Hz, 2H), 1.26 (m, 3H), 1.09 (d, J=7.0 Hz, 18H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.C1COCC1.[N:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH3:26].[C:27](=O)([O:30]C)[O:28][CH3:29]>O>[CH3:26][C:20]1[CH:21]=[C:22]([CH2:25][C:27]([O:28][CH3:29])=[O:30])[CH:23]=[CH:24][N:19]=1
Reactant: Cc1ccnc(C)c1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccnc(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
An LDA-THF solution (2.00 mol/L, 65.0 mL, 130 mmol) was cooled to −78° C., then a THF solution (50.0 mL) of 2,4-lutidine (10.7 g) was added thereto, followed by stirring for 2 hours. Then, the temperature was raised to 0° C., and a THF solution (50.0 mL) of dimethyl carbonate (11.7 g) was added dropwise to the mixture, followed by stirring for 30 minutes. Water was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 2-methylpyridin-4-ylacetate (2.69 g, yield 16%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[O:10]
Reactant: ClCCCBr
Reactant: O=c1[nH]c2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1oc2ccccc2n1CCCCl
Temperature: 55 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of 2-benzoxazolinone (2.0 g, 14.8 mmol) and potassium carbonate (3.07 g, 22.2 mmol) in N,N-dimethylformamide (20 mL), was added 1-bromo-3-chloropropane (4.4 mL, 44.4 mmol, d=1.6). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4 and concentrated to obtain 3-(3-chloropropyl)benzo[d]oxazol-2(3H)-one (3.1 g, 99%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:30]=3[Cl:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Cl)cc4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,4-Dichlorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 537.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH2:31][C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.[BH3-]C#N.[Na+]>CO>[NH:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:31][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([CH2:22][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2nc3ccccc3[nH]2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Using General Procedure A: To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (140 mg, 0.34 mmol) and 2-aminobenzimidazole (45 mg, 0.0.34 mmol) in MeOH (4 mL) was added NaBH3CN (64 mg, 1.1 mmol) and the mixture was stirred at room temperature for 20 hours. Purification of the crude yellow foam by column chromatography on silica gel (200: 1:1—EtOAc:MeOH:NH4OH) followed by radial chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded AMD9693 (26 mg, 15%) as a white solid. 1H NMR (CDCl3) δ 1.57-1.74 (m, 1H), 1.87-2.05 (m, 2H), 2.10-2.20 (m, 1H), 2.63-2.75 (m, 1H), 2.75-2.90 (m, 1H), 3.54 (s, 2H), 3.86 (d, 1H, J=16.8 Hz), 4.03-4.16 (m, 2H), 4.24-4.35 (m, 2H), 5.44 (br s, 1H), 6.88-6.91 (m, 4H), 7.10-7.19 (m, 7H), 7.42 (d, 1H, J=7.5 Hz), 7.54 (br s, 2H), 8.65 (d, 1H, J=4.2 Hz); 13C NMR (CDCl3) δ 21.16, 24.26, 29.10, 46.66, 48.40, 53.29, 60.62, 111.39 (br), 118.11 (br), 120.13, 121.81, 122.37, 127.22, 128.57, 133.86, 134.79, 137.41, 138.17, 143.78, 146.67, 155.56, 156.41, 157.20. ES-MS m/z 514.4 (M+H). Anal. Cald. for C32H31N7.0.8CH2Cl2.0.4C4H8O2: C, 66.98; H, 5.85; N, 15.90. Found: C, 67.14; H, 5.66; N, 15.87.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[CH:9][C:8]=1[F:21])#[N:6].O>ClCCl>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[F:21])#[N:6]
Reactant: COc1ccc(-c2ccc(C#N)c(F)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(-c2ccc(O)cc2)cc1F
Reaction time: 20 h

Procedure:
A solution of boron tribromide (12.0 ml, 31.8 g, 0.13 mol) in dry dichloromethane (100 ml) was added dropwise to a stirred, cooled (-78° C.) solution of compound 4 (14.0 g, 0.06 mol) in dry dichloromethane (250 ml) under dry nitrogen. The stirred mixture was allowed to warm. to room temperature over 20 h (i.e., until glc analysis revealed absence of starting material). Water was added and a yellow precipitate was produced. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to afford a pale-yellow powder.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[S:31][C:32]([CH3:39])=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36]>N.CO>[CH3:29][C:30]1[S:31][C:32]([CH3:39])=[CH:33][C:34]=1[S:35]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)c(C)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.7 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2,5-Dimethylthiophene-3-sulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (3.2 mg). MS m/z 363 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([Br:19])[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:19][C:17]1[CH:16]=[N:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnn(C2CCNCC2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.515 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). The reaction was stirred at room temperature until LCMS indicated completion of the reaction. The solvents were removed in vacuo, and the residue was dissolved in MeOH (15 mL). The pH of the solution was adjusted to 9 with hydroxide resin to afford 4-(4-bromo-pyrazol-1-yl)-piperidine.