Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].[Br-].[Na+].C([Li])CCC.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[C:23]1([CH2:22][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: ClCc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Tetrahydrofuran (125 mL), N-(1,1- dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent) and sodium bromide (1.3 g) are charged and cooled to -40° C. under nitrogen. Two equivalents of nbutyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Benzyl chloride (1.05 equivalents) is then added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 ml) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product may crystallize. Product yield of 94% determined by internal standard assay on gas chromatograph.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([S@@:4]([NH:6][C@:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH2:8][C:9]([OH:11])=O)=[O:5])[CH3:3].[C:20]1([CH3:27])[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][C:2]([CH3:1])([S@@:4]([NH:6][C@:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH2:8][C:9]([NH:26][C:22]1[CH:21]=[C:20]([CH3:27])[CH:25]=[CH:24][CH:23]=1)=[O:11])=[O:5])[CH3:3]
Reactant: CC(C)(C)[S@](=O)N[C@](C)(CC(=O)O)c1ccccc1
Reactant: Cc1cccc(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
To a solution of (R)-3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoic acid (266 mg, 0.94 mmol) in CH2Cl2 (5 mL) was added m-tolylamine (111 mg, 1.03 mmol), DCC (212 mg, 1.03 mmol) and DMAP (11.5 mg, 0.094 mmol) at 0° C. Then the reaction mixture was stirred at room temperature overnight. The residue was purified by preparative TLC to give (R)-3-((S)-1,1-dimethylethylsulfinamido)-3-phenyl-N-m-tolylbutanamide (25 mg, 7%). 1H NMR (CDCl3): 1.10-1.20 (m, 12H), 1.51-1.65 (m, 11H), 3.10-3.30 (m, 2H), 4.25 (s, 1H), 6.80-6.90 (m, 1H), 7.06-7.15 (m, 1H), 7.28-7.48 (m, 5H), 7.50-7.60 (m, 2H), 8.95 (s, 1H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[C:26]3[C:39]([NH2:40])=[N:38][CH:37]=[N:36][C:27]=3[N:28]3[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31][CH2:30][C:29]=23)[CH:16]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O>[NH2:40][C:39]1[C:26]2[C:25]([C:17]3[CH:16]=[N:15][C:24]4[C:19]([CH:18]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:29]3[CH2:30][CH2:31][C@H:32]([NH:35][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:33][CH2:34][N:28]3[C:27]=2[N:36]=[CH:37][N:38]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC[C@@H](N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2CC1
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
N,N-Diisopropylethylamine (0.192 ml) and a solution of acryloyl chloride (83.3 mg) in acetonitrile (0.83 ml) were added to an acetonitrile (1.6 ml)-water (1.6 ml) solution of the (S)-5-(quinolin-3-yl)-7,8,9,10-tetrahydro-6H-pyrimido[5′,4′:4,5]pyrrolo[1,2-a]azepin-4,8-diamine (317 mg) obtained in Step 9 under ice-cooling. After being stirred at the same temperature for 15 minutes, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a light-yellow solid (226 mg).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([O:18][CH2:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C@@:27]23[CH2:34][CH2:33][C:32](=O)[N:31]2[C@@H:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29][O:28]3)[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][CH2:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C@H:27]2[CH2:34][CH2:33][CH2:32][N:31]2[C@@H:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29][OH:28])[CH2:23][CH2:22]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CC[C@@]2([C@H]3CC[C@H](CCOCc4ccccc4)CC3)OC[C@H](c3ccccc3)N12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC[C@H](c1ccccc1)N1CCC[C@@H]1[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) mixture of anhydrous AlCl3 (6.30 g, 47 mmol) in THF (300 mL) is slowly added lithium aluminum hydride (5.95 g, 157 mmol), and the resulting mixture is stirred at the same temperature for 10 min. To the resulting stirred and cooled (−65° C.) THF mixture is added trans-(3S,7aS)-7a-[4-(benzyloxyethyl)cyclohexyl]-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5-one (22.0 g, 52 mmol) dissolved in THF (150 mL) over 30 min. The resulting mixture is stirred at the same temperature for 2 hours, and then warmed to room temperature and stirred additional 1 hour. The resulting mixture is cooled to 0° C., quenched by careful addition of Na2SO4-10H2O, and stirred for additional 30 min at room temperature. The insoluble matter is filtered and the filtrate is concentrated in vacuo to afford crude trans-(S)-2{(R)-2-[4-(benzyloxyethyl)cyclohexyl]pyrrolidin-1-yl}-2-phenylethanol, which is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13]C)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH4+:15].[OH-]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH2:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
Methyl 2-(3-nitrophenyl)acetate (9.6 g, 49 mmol) was treated with conc. NH4OH (24 ml, 172 mmol). The suspension was stirred briskly at RT until complete, then chilled thoroughly in an ice bath. The solids were collected by filtration, rinsed sparingly with ice H2O and dried to yield pure 2-(3-nitrophenyl)acetamide as an off-white solid (7.47 g, 84% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.18-8.02 (m, 2H), 7.75-7.70 (m, 1H), 7.61-7.57 (m, 3H), 7.00 (brs, 1H), 3.58 (s, 3H); MS (ESI) m/z: 181.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:28]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([F:28])=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)F
Temperature: -5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-leucine (0.50 g, 1.87 mmol) and pyridine (0.15 ml, 1.88 mmol) in anhydrous DCM (5 ml) kept under a N2 atmosphere was added cyanuric fluoride (0.51 ml, 5.64 mmol) at −15 to −10° C. A white precipitate formed. After stirring for 1 hr at −5° C., IR of the crude reaction mixture indicated formation of the acyl fluoride. After 2 hrs crushed ice was added along with DCM (10 ml). The organic layer was separated and the aqueous layer extracted with DCM (5 ml). The combined DCM layers were washed with ice-cold water (10 ml), dried (MgSO4) and concentrated under reduced pressure to afford a colourless oil (0.36 g, 73%) which was used in subsequent reactions without further purification: νmax(polyethylene card) 3317 (N—H), 1843 (acid fluoride); δH (200 MHz, CDCl3) 0.97 (6H, d, J 6.0, CH(CH3)2), 1.62–1.78 (3H, m, CH(CH3)2 & CH2CH(CH3)2), 4.54–4.61 (1H, m, NHCH), 5.02 (1H, m, NH), 5.14 (2H, s, CH2Ph), 7.36 (5H, s, Ar—H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccc([N+](=O)[O-])cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-nitrobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-nitrobenzoyl chloride in a similar manner as described above to give an orange solid (32% yield). 1H-NMR (DMSO-d6): δ 11.11 (s, 1H), 9.24 (d, 1H), 8.36 (d, 2H), 8.19 (d, 2H), 7.62 (m, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 5.41 (m, 1H), 2.69 (m, 2H), 2.10 (m, 2H), 1.89 (m, 2H); MS m/z 414 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH:51]2[CH2:56][CH2:55][CH2:54][CH2:53][NH:52]2)[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:52]1[CH2:53][CH2:54][CH2:55][CH2:56][CH:51]1[CH2:50][N:47]1[CH2:46][CH2:45][N:44]([CH3:43])[CH2:49][CH2:48]1)=[O:24]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CN1CCN(CC2CCCCN2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1CCN(CC2CCCCN2C(=O)CCC(Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)c2nc3cc(Cl)ccc3[nH]2)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 2-(4-methyl-piperazin-1-ylmethyl)-piperidine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.COC1C=CC(CNC2CCC2)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: COc1ccc(CNC2CCC2)cc1
Solvent: CO
Product: COc1ccc(CNC2CN(C(=O)OC(C)(C)C)C2)cc1

Procedure:
6A was prepared from 4-methoxybenzaldehyde and tert-butyl 3-aminoazetidine-1-carboxylate following the procedure employed for the preparation of 4A. HPLC: Rt=3.0 min (PHENOMENEX® Luna C18 4.6×30 mm 3 u, 10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=293.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: C1CCNCC1
Product: O=S(=O)(c1cccc(Br)c1)N1CCCCC1

Procedure:
Identical procedure to Step A of Example 1, starting from 3-bromobenzenesulphonyl chloride and piperidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>CN(C=O)C>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cccc(O)c1
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DISC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.[CH3:11][NH:12][C:13](=[S:16])[NH:14][NH2:15].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:11][NH:12][C:13]1[S:16][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)=[N:15][N:14]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CNC(=S)NN
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNc1nnc(-c2cccc(Cl)c2)s1

Procedure:
A well-stirred mixture of 125 g (0.8 mole) of 3-chlorobenzoic acid and 84 g (0.8 mole) of 4-methylthiosemicarbazide in 700 ml of dioxane was heated until the solution was homogeneous. Phosphorus oxychloride (123 g, 0.8 mole) was added dropwise to the resulting solution at a rate to maintain the dioxane at gentle reflux.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[C:19](=[C:21]([CH2:25][CH2:26][CH3:27])[N:22]([CH3:24])[N:23]=3)[N:20]=2)=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]([CH3:40])([CH3:39])[CH2:37]O.C(N(C(C)C)CC)(C)C.S(Cl)(Cl)=O>ClCCl.CN(C)C=O>[CH3:37][C:36]1([CH3:40])[CH2:39][O:11][C:10]([C:9]2[CH:13]=[C:14]([C:15]3[NH:16][C:17](=[O:28])[C:18]4[C:19](=[C:21]([CH2:25][CH2:26][CH3:27])[N:22]([CH3:24])[N:23]=4)[N:20]=3)[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[N:7][CH:8]=2)=[N:35]1
Reactant: CC(C)(N)CO
Reactant: CCCc1c2nc(-c3cc(C(=O)O)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Agent: O=C(Cl)C(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1c2nc(-c3cc(C4=NC(C)(C)CO4)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Reaction time: 2 h

Procedure:
6-Isobutoxy-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-5-yl)nicotinic acid (Example 24) (200 mg, 0.52 mmol) was dissolved in dichloromethane and oxalyl chloride (0.18 mL, 2.8 mmol) was added followed by 1 drop of N,N-dimethylformamide. The mixture was stirred for 2 h and the solvent was then removed in vacuo, azeotroping with further dichloromethane. A dichloromethane solution of the acid chloride was then added to a solution of 2-amino-2-methyl-1-propanol (0.05 mL, 0.52 mmol) and diisopropylethylamine (0.09 mL, 0.62 mmol) in dichloromethane and the mixture stirred for 2 h. The reaction mixture was diluted with further dichloromethane and washed with a 1 N solution of citric acid, followed by brine. The organics were dried (MgSO4) and concentrated in vacuo. The residue was redissolved in dichloromethane and thionyl chloride (0.05 mL, 0.62 mmol) was added. After 2 h the solution was washed with water then sodium bicarbonate solution. The organic phase was dried and concentrated. The crude residue was purified by flash column chromatography (50% ethyl acetate:pentane as eluant) to give the product.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=2)=[N:17][N:16]=[N:15]1.C([O-])(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[NH:17][N:16]=[N:15][N:14]=3)=[CH:26][CH:27]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2ccccc2n1
Yield: 37.5 %

Procedure:
To 50 mL of tetrahydrofuran were added 2,4-dichloroquinazoline (0.30 g). N-[[-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl amine hydrochloride (0.434 g) and 2.0 g of sodium acetate. The resulting suspension was stirred at room temperature for 53 hours at which time all the THF was removed by evaporation. The residue was purified by silica gel chromatography to yield 0.234 g of the desired product. (38%). The product was characterized as its sodium salt: 1H NMR (DMSO-d6, 400 MHz) δ 9.30 (t, J=5.9 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.79 (m, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (m, 2H), 7.32 (m, 3H), 7.18 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 4.72 (d, J=5.8 Hz, 2H); negative FAB MS m/e 412 (M-Na)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:30][C:29]=1[F:28]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
The title compound was prepared in analogy to Example 173, step 1 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) with 3-fluoro-4-methoxycarbonylphenylboronic acid [CAS Reg. No. 505083-04-5]. MS (neg. ion, m/e)=552.5 [(M−H)−].
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH2:9][CH2:8]1.C(N(CC)CC)C>CS(C)=O>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:17]1[CH:18]=[C:19]3[C:14]([C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11][N:10]3[CH:7]3[CH2:9][CH2:8]3)=[CH:15][C:16]=1[F:21])[CH2:2]2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1NCC2CC12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4CC4C3)c(F)cc2c1=O
Yield: 33 %

Procedure:
A solution of the hydrochloride salt of 3-azabicyclo-[3.1.0]hexane (157 mg, 1.31 mmol), (prepared in a manner similar to that described in U.S. Pat. No. 4,183,857) in dimethylsulfoxide (13 ml) was treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (348 mg, 1.31 mmol) and triethylamine (0.58 ml, 3.9 mmol) and heated for 18 hours. Filtration of the reaction mixture provided a white solid, which was purified by column chromatography (eluant: 1% acetic acid in chloroform, then 5% acetic acid in chloroform, then methanol) to give the title product as a white solid, melting point 290° (186 mg, 0.43 mmol, 33% yield). 1H NMR (DMSO-d6) 8.54 (s, 1H), 7.75 (d, J=14 Hz, 1H), 7.08 (d, J=9 Hz, 1H}, 3.83 (dd, J=4, 10 Hz, 2H), 3.73 (bs, 1H), 3.62 (bd, J=10 Hz, 2H), 1.77 (m, 2H), 1.30 (d, J=6 Hz, 2H), 1.14 (bs, 2H), 0.77 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@H:4]([CH:16]([CH3:18])[CH3:17])[NH:5]C(OCC1C=CC=CC=1)=O.[CH2:21]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33]([OH:35])=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>CO.[Pd]>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@H:4]([CH:16]([CH3:18])[CH3:17])[NH:5][C:33](=[O:35])[C@@H:32]1[CH2:36][CH2:37][CH2:38][N:31]1[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:30]
Reactant: COC(OC)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: COC(OC)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(C)C
Temperature: -20 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
24.5 g (0.087 mol) of N-benzyloxycarbonyl-L-valinal dimethyl acetal were dissolved in 200 ml of methanol and the solution was hydrogenated for 2 hours in the presence of 0.5 g of 5% palladium/carbon. After removal of the catalyst by filtration, the solvent was removed by evaporation and the residue was dissolved in 250 ml of dichloromethane. The solution was washed with brine and dried over magnesium sulphate. The solution was then cooled to -20° C. and there were then added 21.8 g (0.087 mol) of N-benzyloxycarbonyl-L-proline followed by 19.8 g (0.096 mol) of N,N'-dicyclohexylcarbodiimide. The solution was stirred at -20° C. for 2 hours and left to stand at 4° C. for 64 hours. The separated N,N'-dicyclohexylurea was removed by filtration and the filtrate was evaporated. The residue was taken up in ethyl acetate, the solution was washed with sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give an oil. The product was purified by chromatography on 250 g of silica gel using ethyl acetate/hexane (1:1) for the elution. Evaporation of the solution yielded 21.9 g (67%) of N-benzyloxycarbonyl-L-prolyl-L-valinal dimethyl acetal; Rf-value (ethyl acetate): 0.63.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:4]=2[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>>[Cl:14][C:12]1[CH:11]=[CH:10][C:5]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)=[N:3][C:4]=2[CH:13]=1
Reactant: CN1CCNCC1
Reactant: CC(C)n1c(Cl)nc2cc(Cl)ccc21
Agent: Cl
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)ccc21
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 46.9 %

Procedure:
A mixture of 2,5-dichloro-1-isopropylbenzimidazole (7 g) and N-methylpiperazine (10 g) was stirred at 140° C. for 3.5 hours. After cooling, 2N hydrochloric acid was added to the mixture and the mixture was washed with ethyl acetate. The 2N hydrochloric acid layer was made basic with an aqueous 2N sodiumhydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole (4.2 g). A part of the obtained product was recrystallized from acetonitrile, which showed the following physical properties:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]#[N:26])=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1>O1CCCC1>[Br:34][C:30]1[CH:29]=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([NH:14][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[CH:16]=3)[N:21]=[CH:20][C:19]=2[C:25]#[N:26])[CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and butyryl chloride (0.380 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed, and the residue was slurried with water and collected. The residue was washed with boiling methanol and dried in vacuo to give 0.773 g of brown powder; mp 276-277 ° C. (dec).