Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][C:16]([N:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=5)[CH2:22][O:21][C:20]4=[O:31])=[N:15][C:14]=23)[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[K+].Cl.[NH:38]([C:40]([NH2:42])=[O:41])[NH2:39]>CCO.CO>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][C:16]([N:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=5)[CH2:22][O:21][C:20]4=[O:31])=[N:15][C:14]=23)[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:39]/[NH:38][C:40]([NH2:42])=[O:41]
Reactant: O=Cc1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cn4)nc23)cc1F
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: NC(=O)N/N=C/c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cn4)nc23)cc1F
Yield: 39 %

Procedure:
A solution of (S)-2-fluoro-4-(5-(4-(5-fluoropyridin-2-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)b enzaldehyde (0.370 g, 0.878 mmol), potassium acetate (0.0948 g, 0.966 mmol) and hydrazinecarboxamide hydrochloride (0.108 g, 0.966 mmol) in 3:1 EtOH/MeOH (6 mL) was stirred at ambient temperature overnight. The solvents were evaporated under vacuum. The residue was purified by preparative TLC (10% MeOH in DCM) to give (S,E)-2-(2-fluoro-4-(5-(4-(5-fluoropyridin-2-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzylidene)hydrazinecarboxamide (0.164 g, 39% yield) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:8][CH2:7][C:6]2[CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=[CH:12][C:5]=2[CH2:4][O:3]1.N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O.O>[C:21]([Si:25]([O:14][CH2:13][C:10]1[CH:11]=[CH:12][C:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:8][CH2:7][C:6]=2[CH:9]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1(C)OCc2ccc(CO)cc2CO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2CO1
Reaction time: 2 h

Procedure:
To a solution of 3.227 g (15.495 mM) of (7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocyclohepten-2-yl)-methanol and 1.27 g (18.6 mM) of imidazole in 20 ml of N,N-dimethylformamide was added 4.69 g (17.0 mM) of tert-butylchlorodiphenylsilane at room temperature and the mixture was stirred for 2 hours. This reaction mixture was poured in water and extracted with 3 portions of diethyl ether. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([C:38]([OH:40])=[O:39])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][CH2:35][C@H:34]([C:38]([OH:40])=[O:39])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC[C@H](C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(S)-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidine-3-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[S-:17].[K+]>C1(C)C(C)=CC=CC=1>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[S:17][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Fc1ccc([S-])c(F)c1
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of 3'-chloro-4'-nitroacetophenone (2.4 g), potassium 2,4-difluorothiophenoxide (2.7 g), and N,Ndimethylformamide (5 ml) in xylene (50 ml) was stirred for 8 hours at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residual solid was recrystallized from ethanol to give prisms of 3'-(2,4-difluorophenylthio)-4'-nitroacetophenone (2.3 g).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])=[O:13])[O:5][C@@H:4]([N:21]2[C:31]3[N:30]=[C:28]([NH2:29])[NH:27][C:25](=[O:26])[C:24]=3[N:23]=[CH:22]2)[CH2:3]1.[C:32]([NH:42][C@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:16][OH:17])[CH2:18][O:19][C:47](=[O:48])[C@H:43]([CH:44]([CH3:45])[CH3:46])[NH:42][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[O:13])[O:5][C@@H:4]([N:21]2[C:31]3[N:30]=[C:28]([NH2:29])[NH:27][C:25](=[O:26])[C:24]=3[N:23]=[CH:22]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](COC(=O)CCC(=O)OC(CO)CO)O2)c(=O)[nH]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(CO)OC(=O)CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dihydroxy-2-propyloxy carbonyl)-propanoyl]guanosine (1.3 g, 2.93 mmole), N-CBZ-L-valine (1.00 g, 4 mmole), HOBT (0.54 g, 4 mmole) and DMAP (48.8 mg, 0.4 mmole) was coevaporated two times with DMF and reduced to about 60 ml. DCC (0.91 g, 4.4 mmole) was added and the mixture was stirred for 72 hours at room temperature. The mixture was filtered and the solution evaporated under reduced pressure. Ethyl acetate (150 ml) was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.99 g
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([CH2:26]OS(C)(=O)=O)=[CH:24][CH:23]=1)=[O:19]>O>[N:10]1[C:11]2[CH:2]([NH:1][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=4)=[O:19])=[CH:33][CH:32]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)OCc1ccc(CNC(=O)c2ccccn2)cc1
Reactant: NC1CCCc2cccnc21
Solvent: O
Product: O=C(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Using General procedure H: Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (148 mg, 1.00 mmol) with methanesulfonic acid 4-{[(pyridine-2-carbonyl)-amino]-methyl}-benzyl ester (214 mg, 0.67 mmol) for 3 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 48:1:1) gave AMD9397 (81 mg, 33%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.72-1.83 (m, 2H), 2 00-2.06 (m, 1H), 2.16-2.20 (m, 1H), 2.75-2.83 (m, 2H), 3.82-3.84 (m, 1H), 3.88 (d, 1H), J=13.2 Hz), 3.98 (d, 1H, J=12.9 Hz), 4.65 (d, 2H, J=6.0 Hz), 7.05-7.06 (m, 1H), 7.32-7.42 (m, 6H), 7.85 (ddd, 1H, J=7.8, 7.8, 1.8 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.34 (br s, 1H), 8.37 (d, 1H, J=3.3 Hz), 8.52 (d, 1H, J=3.9 Hz). 13C NMR (75.5 MHz, CDCl3) δ 20.05, 29.00, 29.24, 43.68, 51.85, 57.85, 122.19, 122.70, 126.56, 128.37 (2C), 129.01 (2C), 132.83, 137.07, 137.23, 137.73, 140.41, 147.20, 148.46, 150.23, 157.82, 164.57. ES-MS m/z 373 (M+H). Anal. Calcd. for C23 H24N4O•0.3 H2O: C, 73.11; H, 6.56; N, 14.83. Found: C, 72.98; H, 6.58; N, 14.63.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:8]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Tert-Butyl 3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate (from Step 5) was dissolved in DMF (0.18 M). NaH (60% suspension in mineral oil, 1.5 eq.) was added and the resultant mixture stirred for 5 min at RT, then for another 5 min at 50° C. The solution was allowed to reach RT, and then neat 2-chloro-N,N-dimethylacetamide (1.6 eq.) was added dropwise. After 1 h analytical RP HPLC indicated complete conversion of the starting material. The mixture was diluted with EtOAc, and then washed with water (3×) and brine. Drying over Na2SO4 and evaporation gave a colorless solid, which was purified by flash chromatography on silica gel using PE/EtOAc (3:1, then 2:1) as the eluent. The resulting colorless solid was immediately dissolved in a mixture of DCM and TFA (0.05 M, 1:1, v/v). After stirring for 30 min at RT, the solvents were removed in vacuo to give after drying under high-vacuum, the title compound as a light yellow foam. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.12-1.31 (m, 3H), 1.60-1.75 (m, 5H), 1.80-1.92 (m, 2H), 2.53-2.59 (m, 1H), 2.80 (s, 3H), 2.89 (s, 3H), 4.84 (s, 2H), 7.31 (d, J 6.4, 2H), 7.48-7.53 (m, 3H), 7.64 (d, J 8.4, 1H), 7.81 (d, J 8.4, 1H), 7.92 (s, 1H,); MS (ES+) m/z 405 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:30])[C:3]=1[OH:31].O[C@@H:33]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([O:36]C)=[O:35].BrBr>C(Cl)(Cl)Cl>[Br:30][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:31][C@H:33]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([OH:36])=[O:35]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 13) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: opt. rot. [a]25/D=+22.84° (10.068 mg/mL, CHCl3); NMR (DMSO-d6); δ 13.13 (broad s, 1H), 8.42 (d, J=8 Hz, 1H), 7.75 (t, J=2 Hz, 2H), 7.58 (ddd, J=8, 7, 1 Hz, 1H), 7.50 (ddd, J=8, 7, 1 Hz, 1H), 7.44 (d, J=8 Hz, 1H), 7.37-7.19 (m, 7H), 7.15-7.11 (m, 1H), 7.03-7.00 (m, 2H), 5.22 (t, J=7 Hz, 1H), 3.37-3.28 (m, 2H), 2.39 (s, 3H), 1.62 (s, 3H); MS (EI): [M+], 2 bromine isotope pattern, 716 (10%), 718 (20%), 720 (10%); Anal. Calc. for C35H26Br2O3S2: C, 58.50, H, 3.65, N, 0.00. Found: C, 58.77, H, 3.94, N, 0.16.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.Cl.Cl.[NH2:17][NH2:18]>N>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH:8]=[CH:9][C:10](=[O:11])[NH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C=CC(=O)c1ccc(F)cc1
Reactant: NN
Agent: Cl
Agent: N
Product: O=c1ccc(-c2ccc(F)cc2)n[nH]1
Yield: 93.7 %

Procedure:
3-(4'-Fluorobenzoyl)-acrylic acid (9.7 g, 0.04996 mol) was dissolved in 50 ml of concentrated aqueous ammonia solution, and the solution was allowed to stand for a few days, without a cover. The solution was first rendered neutral by adding hydrochloric acid (concentrated, 30 ml), a further 20 ml of concentrated hydrochloric acid were then added, followed by hydrazine hydrochloride (4.1 g, 0.06 mol), after which the mixture was refluxed for 8 hours. After cooling, the solid product which had precipitated was isolated, washed with water and dried to constant weight. 3-(4'-Fluorophenyl)-6-pyridazinone of m.p.=265°-267° C., 8.9 g, 0.04680 mol, were obtained, which corresponds to a yield of 93.7% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](F)[C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[H-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:19])=[C:11]([CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:20]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1F
Temperature: 0 °C
Reaction time: 9 h
Yield: 94.8 %

Procedure:
In THF (100 ml) were dissolved 1-benzyloxy-2,3-difluoro-6-nitrobenzene (4.17 g, 15.7 mmol) and di-tert-butyl malonate (3.52 ml, 15.7 mmol). To the resulting solution was added sodium hydride (60% in oil, 1.26 g, 31.4 mmol) in portions under stirring at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and then at 80° C. for 9 hours. Di-tert-butyl malonate (7.04 ml, 31.4 mmol) and sodium hydride (60%; 2.52 g, 52.8 mmol) were added and the mixture was stirred at 80° C. for 2 days. After cooling to room temperature, the reaction mixture was poured in ice water (100 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 200 g), whereby from hexane/ethyl acetate (8/1) eluate fractions, the title compound (6.87 g, 95%) was obtained as an orange solid.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[C:9]1([CH2:18][CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br>ClCCl.C(O)(=O)C>[CH2:18]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17])[CH3:19]
Reactant: CCC1(C2=C(Br)C(=O)CCC2)CCCCN(C)C1=O
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Reaction time: 3 h

Procedure:
A solution of 3-(2-bromo-3-oxocyclohex-1-enyl)-3-ethylhexahydro-1-methylazepin-2-one (6.57 g) in dichloromethane (70 ml) was treated with 48% HBr in acetic acid (1 ml). After 3 hours NMR indicated completion. The solvent was removed under reduced pressure and the residue triturated with aqueous ammonia to yield the title compound as a white crystalline solid, m.p. 178°-80° C. (EtOAc).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:26][CH:25]=4)[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]5[CH2:34][CH2:35][CH2:36][CH2:37]5)=[CH:26][CH:25]=4)[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 2 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-carbamic acid tert-butyl ester (1.39 g, 2.71 mmol) was dissolved in dichloromethane (10 ml). Trifluoroacetic acid (10 ml) was added and the reaction mixture stirred for 2 hours. Neutralisation was performed by adding saturated aqueous sodium hydrogencarbonate. The aqueous phase was extracted twice with dichloromethane, and the combined organics washed with brine, dried over anhydrous magnesium sulgate, filtered and concentrated in vacuo to give the desired compound. Yield 830 mg, 74%. 50 mg was purified by preparatory LCMS.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[C:4]([F:14])[CH:3]=1.CO.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:17]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[C:4]([F:14])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: COC(=O)C(C)c1ccc(N)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(NC2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.50 g (7.6 mmol) of compound (7) in a solvent mixture of 10 mL of methanol and 0.2 mL of acetic acid, 1.4 mL (15.2 mmol) of cyclopentanone and 0.96 g (15.2 mmol) of sodium cyanoborohydride (NaBH3CN) were added. The obtained solution was stirred at room temperature for 12 hours. Next, the reaction mixture was dried under a vacuum and extracted with dichloromethane, followed by drying over anhydrous sodium sulfate and subsequent filtration. The filtrate was dried under a vacuum, and the residue was purified by silica gel chromatograph (n-hexane/ethyl acetate 3:2) to give a methyl ester of compound (11a). This compound was hydrolyzed with sodium hydroxide to give 1.09 g (yield 54%) of compound (11a) of interest as brown powder.
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:39])[N:31]=[C:30]([C:40]([C:46]([F:49])([F:48])[F:47])([C:42]([F:45])([F:44])[F:43])[OH:41])[CH2:29]3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])C)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[N:32]1[CH:28]([C:25]2[CH:24]=[CH:23][C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH2:12][CH2:11][CH2:10][NH:8][CH3:1])(=[O:15])=[O:14])[CH:17]=3)=[CH:27][CH:26]=2)[CH2:29][C:30]([C:40]([C:46]([F:49])([F:47])[F:48])([C:42]([F:43])([F:45])[F:44])[OH:41])=[N:31]1
Reactant: CN(CCCS(=O)(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCS(=O)(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.7 %

Procedure:
To 5-{3′-[3-(N-BOC-N-methyl-amino)-propane-1-sulfonyl]-biphenyl-4-yl}-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (9.0 mg, 0.012 mmol) prepared in Example 285, were added dichloromethane (0.5 mL) and trifluoroacetic acid (9.0 uL, 0.12 mmol). The reaction mixture was stirred at room temperature for 48 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([C:20]4[CH:24]=[CH:23][S:22][CH:21]=4)[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[C:34]([C:35]([N:17]2[CH2:18][CH:19]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:13][CH2:12]3)[CH2:16]2)=[O:36])=[CH:38][CH:39]=[CH:40][N:41]=1
Reactant: Fc1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Cl)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(c2ccsc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A mixture of 0.105 g (0.3 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine, 0.082 mL (0.6 mmol) of triethylamine and 0.054 g (0.3 mmol) of 2-chloronicotinoyl chloride (Aldrich) in 6 mL of CH2Cl2 was stirred at rt for 4 h. The reaction mixture was concentrated and the residue was purified by chomatography (silica, hexanes: acetone=3:1) to afford 0.12 g of the title compound.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Br:8][C:9]1[C:10]([O:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:11][C:12]2[N:13]([N:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=1[NH2:15].C(N(CC)CC)C>CN(C=O)C>[Br:8][C:9]1[C:10]([O:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])[CH2:35][CH2:36]2)=[N:11][C:12]2[N:13]([N:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=1[NH2:15]
Reactant: Nc1c(Br)c(OCC2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1c(Br)c(OCC2CCN(S(=O)(=O)C3CC3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
Cyclopropanesulfonyl chloride (24 mg, 0.167 mmol) was added into a solution of 6-bromo-5-(piperidin-4-ylmethoxy)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 0.111 mmol) and triethylamine (56 mg, 0.553 mmol) in DMF at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h, concentrated and purified by prep-LC to afford the title compound (21.5 mg): LC/MS RT=4.17 min. Mass calculated for, M+H 557.09, observed 557.09.
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([S:28][CH3:29])=[CH:22]2)=[O:18].[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH:33]=O>C(Cl)Cl>[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH2:33][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:20]=2)[NH:24][C:23]=1[S:28][CH3:29]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2[nH]c(SC)cc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(SC)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
To a methylene chloride (10 ml) solution of trifluoroacetic acid (1.238 g) and triethylsilane (2.52 g), added is a methylene chloride (10 ml) solution of 5-methoxycarbonyl-2-methylthioindole (0.800 g), which had been prepared according to the method described in “Tetrahedron, 42 (16), 4511 (1986)”, and 2,4-dichlorobenzaldehyde (0.760 g), in an ice-water bath. This is stirred for 3 hours in the ice-water bath. The crystal formed is taken out through filtration and dried to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonyl-2-methylthioindole (152) (0.727 g).