Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]C(Br)(Br)Br>ClCCl>[Br:34][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: O=C1Nc2ccccc2OC1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2OC1CCBr
Reaction time: 12 h
Yield: 79 %

Procedure:
580 mg of 2-(2-hydroxyethyl)-1,4-benzoxazin-3-one is stirred with 1 equivalent each of triphenylphosphine and tetrabromomethane in 50 ml of dichloromethane. After 12 hours at room temperature, the reaction is completed. The mixture is concentrated by evaporation, and all of this is put onto a column. After column chromatography, the title compound is obtained in a yield of 79%. [1H]-NMR (CDCl3): 8.35 broad 1H, 7.05 to 6.8 m 4H, 4.77 dd 1H, 3.67 m 2H, 2.5 m 2H.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][CH:12]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCCC.O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][CH:12]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCCCCOCc1ccccc1
Reactant: CCCCC=Cc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC=Cc1cccc(CCCCCOCc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
At -78° C., 27.8 ml of t-butyl lithium (1.7M) in hexane are added to 5.30 gm of 3-bromo-(1-hexenyl)benzene in 75 mls of tetrahydrofuran. The reaction is stirred for 10 minutes, and then 1.1 ml of Li2CuCl3 (0.20M/THF) is added followed dropwise by 5.78 grams of 1-bromo-5-benzyloxy pentane. After allowing the reaction mixture to come to ambient temperature over 5 hours and stirring for an additional 24 hours, silica gel is added; and the mixture is concentrated and then chromatographed (HPLC) to yield pure 3-(5-benzyloxypentyl)-1-(1-hexenyl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:18]=1[O:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:18]=3[O:19][C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cc(F)ccc2N)C1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C

Procedure:
Prepared analogously to example 65.1. from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (R)-tert-butyl 3-(2-amino-5-fluorophenoxy)piperidine-1-carboxylate (Intermediate II).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]([C:20]1[CH:21]=[C:22]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1)([CH3:19])[CH3:18].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH:9]1[C:14]([N:29]1[CH2:28][CH:27]=[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH:17]([CH3:19])[CH3:18])[CH:21]=2)[CH2:31][CH2:30]1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1cccc(C2=CCNCC2)c1
Reactant: CC(C)(C)OC(=O)C1CCCNC1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cccc(C2=CCN(C(=O)C3NCCCC3C(=O)OC(C)(C)C)CC2)c1

Procedure:
To a 0° C. solution of piperidine-2,3-dicarboxylic acid 3-tert-butyl ester (100 mg) in DMF (0.6 mL) was added sequentially, 4-(3-isopropyl-phenyl)-1,2,3,6-tetrahydro-pyridine (97 mg), PyBOP (232 mg), and diisopropylethylamine (0.152 mL). The resultant mixture was stirred at rt overnight. The reaction solution was diluted with EtOAc and washed with saturated NaHCO3 solution (×3), water, and brine. The organic layers were dried over MgSO4, filtered, and concentrated to dry under reduced pressure. The residue was used in next step without further purifications. MS (ESI): 413.2 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:29][CH3:30])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:32]([CH3:47])[CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46]>CCN(CC)CC>[CH3:30][O:29][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:32]([CH3:47])[CH2:33][CH2:34][CH2:35][N:36]3[C:40](=[O:41])[C:39]4=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]4[C:37]3=[O:46])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(9-phenylnonoxy) quinoline (0.85 g, 0.002 mol) and 4-bromo-1-phthalimidopentane (BPP) (2.4 g, 0.008 mol) was heated at 125°-135° C. while Et3N (1 ml) was added in small portions during 0.5 hr. After 2 h, second portions of BPP (0.6 g) and Et3N (2 drops) were introduced. Identical additions of BPP (0.6 g) and Et3N (2 drops were made three more times at 1 h intervals. The mixture was allowed to cool, extracted with Et2O and the extract was treated with Darco and evaporated to dryness. The residue was redissolved in Et2O (100 ml) and treated with an excess of ethereal hydrogen chloride. The resulting dark red precipitate was separated by decantation, basified with ethereal Et3N and the solvent was evaporated. The residual brown oil was dissolved in CHCl3, placed on a silica gel column (100 g) and eluted with CHCl3. Concentration of the eluate provided 0.9 g (72%) of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(9-phenylnonoxy) quinoline as a pale brown oil which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:32][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3)CC2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution [6-fluoro-3-methyl-4-(1-phenylmethanesulfonyl-piperidin-4-yl)-naphthalen-2-yl]-acetic acid methyl ester (82 mg, 0.175 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (83.8 mg, 2 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. After this time, the reaction mixture was diluted with water (˜20 mL) and then acidified with 1.0 N aqueous HCl (3.5 mL). The resulting white precipitate was collected by vacuum filtration, washed with hexanes, and then further dried under vacuum to provide [6-fluoro-3-methyl-4-(1-phenylmethane-sulfonyl-piperidin-4-yl)-naphthalen-2-yl]-acetic acid (50 mg, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br. s., 1H), 7.90 (dd, J=9.03, 6.53 Hz, 1H), 7.80-8.13 (m, 1H), 7.69 (s, 1H), 7.31-7.53 (m, 6H), 4.49 (br. s., 2H), 3.66-3.85 (m, 4H), 3.46-3.57 (m, 1H), 2.87-3.20 (m, 2H), 2.41 (br. s., 3H), 2.13-2.37 (m, 2H), 1.61-1.71 (m, 2H). MS cald. for C25H27FNO4S [(M+H)+]: 456, obsd. 456.2.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:37][CH:36]([N:38]([CH3:40])[CH3:39])[C:33]4([CH2:35][CH2:34]4)[CH2:32]3)[N:27]=[C:26]([CH2:41][CH3:42])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:37][CH:36]([N:38]([CH3:40])[CH3:39])[C:33]4([CH2:35][CH2:34]4)[CH2:32]3)[N:27]=[C:26]([CH2:41][CH3:42])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CC(N(C)C)C3(CC3)C2)n1
Agent: [Pd]
Solvent: CO
Product: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC(N(C)C)C3(CC3)C2)n1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-2-ethyl-5-fluoro-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1058 g, 0.182 mmol) in MeOH (5 mL) was added 10% Pd/C (50% water, 32 mg). The mixture was hydrogenated under balloon pressure for 1 h, and then filtered. The solution was concentrated in vacuo, and the residue was azeotroped with EtOAc and crystallized from EtOAc-hexanes to afford [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-2-ethyl-5-fluoro-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (0.0795 g, 89% yield, mixture of diastereomers) as a white solid. LCMS: (M+H)+: 492.3.
Reaction SMILES: Cl.[C:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[NH:4])[NH2:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:37])[C:23](=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=1)[C:24](=O)[CH3:25].C[O-].[Na+]>C(O)C>[NH2:4][C:2]1[NH:3][C:24]([CH3:25])=[C:23]([C:22](=[O:37])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=N)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCCCCCCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=C(C(=O)CCCCCCCCCCBr)C1c1cccc([N+](=O)[O-])c1

Procedure:
12.7 g of ethyl amidinoacetate hydrochloride and 33.4 g of 14-bromo-3-(3-nitrobenzylidene)tetradecane-2,4-dione are dissolved in 300 ml of ethanol and the solution is treated with 14.5 ml of a 5.25M of sodium methoxide solution. The mixture is heated to boiling under reflux for 7 h and then concentrated in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with water, dried over sodium sulfate, filtered and concentrated again. The oily residue is dried in vacuo and reacted in the next stage without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C@@H:8]([OH:10])[CH3:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-])=O>CO.[Pd]>[NH2:11][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C@@H:8]([OH:10])[CH3:9])[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])cnn1C[C@H](C)O
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cnn1C[C@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.5 %

Procedure:
To a solution of (S)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol (100 mg, 0.54 mmol) in methanol (20 mL) was added 10% Pd/C (20 mg). The reaction mixture was stirred under 1 atm H2 atmosphere at room temperature overnight, and filtered through a pad of Celite. The filtrate was concentrated to give (S)-1-(4-amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol (96 mg, crude) as a yellowish oil. MS (ES+) C7H13N3O requires: 155, found: 156 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[C:19]([N+:31]([O-:33])=[O:32])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([N+:31]([O-:33])=[O:32])[CH:18]=2)[CH2:15][CH2:16]1)([CH3:10])[CH3:9]
Reactant: CC(C)N1CCN(c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115 %

Procedure:
TFA (3 mL) was slowly added to a stirred solution of tert-butyl (4-(4-isopropylpiperazin-1-yl)-2-nitrophenyl)carbamate (1.2 g, 3.29 mmol) in dry DCM (5 mL) under argon atmosphere at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 12 hr. Reaction progress was monitored by LCMS, after completion of the reaction, excess solvents were removed under reduced pressure to afford a crude residue. The crude residue was repeatedly washed with ether to get the title compound (1 g, yield: 80.6%) as a red solid. MS (ESI): 265.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][C:34]([C:37]([O:39]C)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 60 °C
Yield: 69.2 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (106 mg, 0.16 mmol) in methanol (6 mL) was added a solution of NaOH (30 mg, 0.75 mmol) in water (3 mL). The mixture was heated at 60° C. for 5 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 2 with aqueous HCl solution. The precipitate was collected and dried to give title product as a white solid (70 mg). m/z (M+H)+: 631
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:29](=[O:33])[C:30]([NH2:32])=[O:31])=[C:9]([CH3:28])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.CO.[Na]>[OH-].[Na+]>[NH2:32][C:30](=[O:31])[C:29]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:9]=1[CH3:28])=[O:33]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccc(-c2ccccc2)cc1
Yield: 77.1 %

Procedure:
Using the procedure described in Example 2, Part E, 803 mg (1.8 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester was hydrolyzed in 10 mL of 1N NaOH and 20 mL of MeOH to give 614 mg (741% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid, sodium salt, mp, >265° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH:11](=[N:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cc(N=Cc2ccccc2)c(F)cc1Cl
Yield: 94.5 %

Procedure:
A 50-ml four-neck flask equipped with a dehydrating column was charged with 5-amino-2-chloro-4-fluorophenol (1 g), benzaldehyde (0.68 g), p-toluenesulfonic acid (10 mg) and toluene (50 g). The mixture was dehydrated under reflux under normal pressure for 5 hours, and then concentrated under reduced pressure. The precipitated crystals were filtered and washed with a small amount of hexane to give 1.46 g of 5-benzylidenamino-2-chloro-4-fluorophenol as pale brown needle crystals (yield, 94.5%), m.p., 157°-159° C.; MS (m/z) 249 (M+) 172; NMR (CDCl3, δ): 5.1-5.8 (broad, 1H), 6.83 (d, 1H, J=7.6 Hz), 7.15 (d, 1H, J=9.6 Hz), 7.4-7.6 (m, 3H), 7.8-8.0 (m, 2H), 8.47 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:32]=1>>[CH3:36][S:33]([C:31]1[CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=[N:29][CH:30]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (300 mg, 1.0 mmol) and 3-Bromo-5-methanesulfonyl-pyridine (example B.19) (212 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (350 mg, 68%). MS (ISP) 511.1 [(M+H)+]; mp 241-242° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C1CNCCN1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CCN1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-piperazinone according to conditions described in general procedure C. Mp: 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 1.62-1.69 (m, 6 H), 3.25-3.28 (m, 6 H), 3.82 (s, 2 H), 4.14 (s, 2 H), 6.20 (d, J=5.5 Hz, 1 H), 6.38 (s, 1 H), 6.76 (d, J=11.7 Hz, 1 H), 7.00 (d, J=8.0 Hz, 1 H), 7.26 (d, J=8.0 Hz, 1 H), 7.32 (s, 1 H), 7.46-7.55 (m, 2 H), 7.83-7.92 (m, 3 H), 8.20-8.21 (m, 1H), 8.36 (s, 1 H).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[Cl:5][CH2:6][C:7]1([CH3:10])[CH2:9][O:8]1>O>[Cl:5][CH2:6][C:7]1([CH3:10])[O:8][C:2](=[O:1])[NH:3][CH2:9]1
Reactant: N#C[O-]
Reactant: CC1(CCl)CO1
Agent: [K+]
Solvent: O
Product: CC1(CCl)CNC(=O)O1
Reaction time: 15 h

Procedure:
Potassium cyanate (7.61 g) was dissolved in 350 ml of water, and 2-(chloromethyl)-2-methyloxirane was slowly added (5.00 g). The solution was stirred overnight (15 h) at reflux. The reaction mixture was then extracted while still moderately warm with ethyl acetate (5×200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the title compound an off-white solid (3.32 g, 47%). Mass spectrum (ESI) 150.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 5.23 (bs, 1H), 3.70 (d, J=8.7 Hz, 1H), 3.68 (d, J=11.0 Hz, 1H), 3.56 (d, J=11.2 Hz, 1H), 3.34 (d, J=8.9 Hz, 1H), 1.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([O:15]C)[CH:3]=1>Br>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([OH:15])[CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1OC
Agent: Br
Product: O=C(O)COc1ccc(Cl)cc1O

Procedure:
A mixture of the product from step (i) (2.7 g) in 48% aqueous hydrogen bromide (30 ml) was heated under reflux for 2 h. The solvent was evaporated, the residue washed with water and dried, yield 1.7 g.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=O)=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10](C(OC)=O)=[CH:9][CH:8]=1.O.OS(O)(=O)=O.C1C[O:36][CH2:35]C1>>[OH:36][CH2:35][C:20]1([CH2:23][OH:25])[CH:19]=[CH:18][C:17]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH2:21]1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: OCC1(CO)C=CC(c2ccccc2)=CC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
In a 1000 ml three-necked flask, fitted with an efficient condenser, a thermometer and a dropping funnel, is placed a suspension of 6,2 g (0.144 mol) LiAlH4 in 80 ml dry THF under an inert atmosphere. A solution of 30 g (0.122 mol) dimethyl 4,4'-biphenyldicarboxylate in 250 ml dry THF is added dropwise over a period of 30 minutes. The mixture is refluxed with stirring for 1 hour. The mixture is cooled to -20° C. and 80 ml of H2O is added dropwise, followed by slow addition of 80 ml of 20% H2SO4 (aq.). The THF is evaporated under reduced pressure to give a suspension of colourless product in aqueous acid. The product is filtered and washed with H2O. After recrystallisation from aceton, white crystals are obtained. Yield: 93%; melting point: 187.3° C.-188.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:17][C:18]([C:20]2[CH:25]=[C:24]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:21]=2)=[O:19])[CH2:14][CH2:15][OH:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:49]([O:51][C:52](=[O:55])[CH2:53]Br)[CH3:50]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:17][C:18]([C:20]2[CH:25]=[C:24]([O:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:21]=2)=[O:19])[CH2:14][CH2:15][O:16][CH2:53][C:52]([O:51][CH2:49][CH3:50])=[O:55])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCO)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)COCC[C@H](NC(=O)c1cc(OC2CCCC2)nc(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-{(S)-2-[(6-cyclopentyloxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-4-hydroxy-butyryl}-piperazine-1-carboxylic acid ethyl ester (16.8 mg) was dissolved in THF (1 ml) under argon and cooled to 0° C. A solution of potassium bis-(trimethylsilyl)-amide (0.5 M in toluene, 8 μl) and, 5 min later, ethylbromoacetate (5 μl) were added. The mixture was stirred at 0° C. for 1 h and evaporated off. The residue was taken up in water and extracted twice with EA. The org. layers were washed with water, a NaCl solution, dried (Na2SO4) and evaporated off to give 19 mg of the desired compound.