Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:40][CH2:41][CH3:42])=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:41]([O:40][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:2]2[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:3]=2)=[C:37]2[C:33]=1[CH2:34][N:35]([CH3:39])[C:36]2=[O:38])[CH3:42]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CCOc1ccc(N)c2c1CN(C)C2=O
Product: CCOc1ccc(Nc2nc(Nc3ccc(CP(=O)(OCC)OCC)cc3)ncc2C(F)(F)F)c2c1CN(C)C2=O

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-4-ethoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 206A). MS (ES+): m/z 594.25 (100) [MH+]; HPLC: tR=1.14 min (UPLC, purity).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([OH:13])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:13])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1c[nH]c2ccc(F)cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccc(F)cc12
Yield: 83 %

Procedure:
To a solution of 5.1 g of 5-fluoroindole-3-carboxylic acid in 150 ml of tetrahydrofuran were added 5.5 g of 4-amino-1-benzylpiperidine and 5.8 g of dicyclohexylcarbodiimide, and the whole mixture was refluxed under heating on a water bath for 3 hours. After completion of the reaction, the precipitated dicyclohexylurea and a part of the objective product were filtered and suspended in 200 ml of hot tetrahydrofuran. The suspension was stirred and the insoluble dicyclohexylurea was filtered off with suction. The combined filtrates were concentrated and the residue was crystallized with ethyl acetate. The resulting crystals were filtered to give 8.3 g of N-(1-benzyl-4-piperidyl)-5-fluoroindole-3-carboxamide. The product, when recrystallized from a mixture of ethyl acetate and ethanol, melts at 215°-217° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[N:12]1([C:2]2[N:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1ncc2ccccc2n1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: c1ccc2nc(N3CCNCC3)ncc2c1
Temperature: 0 °C

Procedure:
A solution of 2-chloroquinazoline (5 g) in 20 mL of toluene is added dropwise to a refluxing solution of piperazine (20 g) in 150 mL of toluene and the resultant solution refluxed for an additional 24 h. After cooling to 0° C. for 0.5 h, the solution is filtered and the filtrate extracted with 10% acetic acid. The aqueous extracts are washed with ether, basified and extracted with toluene. The toluene layer is then washed with water, dried and concentrated. Finally, the material is placed under vacuum overnight (6.8 g, m.p. 188-121° C.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[N:7]=2)[CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(N)n2)C1

Procedure:
[1-(6-amino-5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was synthesized from 6-chloro-3-nitro-pyridine-2-yl-amine by using the procedure as described in step 1 in Example 160 with the only change being pyrrolidin-3-yl-carbamic acid tert-butyl ester was used as the amine. The intermediate A had following spectral properties.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[C:12](=[O:20])[CH:13]=[CH:14][C:15](=[O:19])[C:16]=1[O:17][CH3:18]>CO.O>[CH3:18][O:17][C:16]1[C:11]([O:10][CH3:9])=[C:12]([OH:20])[CH:13]=[CH:14][C:15]=1[OH:19]
Reactant: COC1=C(OC)C(=O)C=CC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(O)ccc(O)c1OC
Yield: 39.5 %

Procedure:
Sodium hydrosulphite (Na2S2O4, 26 g) was added portionwise to a stirred solution of 2,3-dimethoxy-1,4-benzoquinone (J. Med. Chem., 1971, 14, 45; 5 g) in a mixture of methanol (50 ml) and water (100 ml). The resultant mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give 2,3-dimethoxyhydroquinone (2 g); NMR Spectrum: (CD3SOCD3) 3.71 (s, 6H), 6.37 (s, 2H), 8.47 (s, 2H).
Reaction SMILES: C([O:4][C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(C)C>C(Cl)Cl>[OH:4][C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COc1ccc2cc(C)sc2c1OC(C)C
Solvent: ClCCl
Product: COc1ccc2cc(C)sc2c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 140.1 %

Procedure:
To a mixture of the product of Step D (0.033 g; 0.0941 mmol) in CH2Cl2 (1 ml) TiCl4 (0.02 ml; 0.182 mmol) was added at room temperature under N2. After stirring for 10 min at room temperature, the mixture was diluted to 15 ml with CH2Cl2 and quenched with H2O (5 ml) and the organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure to give 7-hydroxy-6-methoxy-2-methyl-benzo[b]thiophene (0.0256 g; 100%). This was diluted to 1. ml with CH2Cl2 and tosyl chloride (0.03 g; 0.158 mmol), followed by triethylamine 0.022 ml; 0.158 mmol) of were added to it. The resulting mixture was stirred for 1 h at room temperature, washed with H2O, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from hexane/ethyl acetate mixture (9.5:0.5) to give the title compound (0.035 g; 68%), as creamy crystals. 1H-NMR (CDCl3) 2.45 (s, 3H); 2.48 (s, 3H); 3.63 (s, 3H); 6.83 (s, 1H); 7.32 (d, 2H, J=8.27 Hz); 7.43 (d, 1H, J=8.62 Hz), 7.87 (d, 2H, J=8.62 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])=[CH:17][CH:18]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:40])([CH3:41])[CH3:42])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])=[CH:17][CH:18]=1)[CH3:9]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
Trifluoroacetic acid (0.03 mL) was added to a solution of {6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester (Example 23-(2); 2.1 mg, 0.0033 mmol) in dichloromethane (0.15 mL) at room temperature, and the mixture was stirred at room temperature for one hour and 15 minutes. The solvent in the reaction solution was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (1.7 mg, 100%).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([NH:28][C:29]([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[N:10]=[N:9][C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:21][CH2:20]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(C(=O)Nc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (60 mg, 0.21 mmol)) in CH2Cl2 (5 mL) at 25° C. is added phenyl isocyanate (33 mg, 0.28 mmol). After being stirred at 25° C. for 2 h, the reaction mixture is concentrated and purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid phenylamide (49 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)[CH2:11][CH2:10]1)=[O:5].[C:40](Cl)(=[O:44])[O:41][CH2:42][CH3:43]>>[CH2:42]([O:41][C:40]([NH:1][C:2]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)[CH2:11][CH2:10]1)=[O:5])=[O:44])[CH3:43]
Reactant: COc1cc2nc(N3CCOCC3)nc(N3CCC(CCNC(=O)c4cc(C)ccc4N)CC3)c2cc1OC
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc(C)cc1C(=O)NCCC1CCN(c2nc(N3CCOCC3)nc3cc(OC)c(OC)cc23)CC1
Temperature: 25 °C

Procedure:
Ethyl chlorocarbonate (10 ml) was added to 540 mg (1.01 mmol) of 4-[2-(2-amino-5-methylbenzoylamino)ethyl]-1-(6,7-dimethoxy-2-morpholino-4-quinazolinyl)piperidine (Compound 1) obtained in Reference Example 13, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, followed by addition of hexane and ether to the residue. The precipitated crystals were collected by filtration to give 430 mg of crude 4-[2-(2-ethoxycarbonylamino-5-methylbenzoylamino)ethyl]-1-(6,7-dimethoxy-2-morpholino-4-quinazolinyl)piperidine, which was then dissolved in 10 ml of ethanol. To the solution was added 210 mg of potassium hydroxide, and the mixture was heated under reflux for one hour. After evaporation of the solvent under reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was washed and dried, and the solvent was evaporated to give 360 mg (overall yield: 64%) of Compound 29 as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.N>N1C=CC=CC=1.O>[CH3:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(-c2ccccc2)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g (0.012 mole) of crude product of 3-amino-4-methylaminoquinoline was dissolved in 20 ml of pyridine, and 1.5 ml (0.013 mole) of benzoyl chloride was added followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and 20 ml of phosphorus oxychloride was added to the concentrate, followed by refluxing with heating for 3 hours. The residues obtained by concentration under reduced pressure were dissolved in water and the solution was made alkaline with ammonia water. The precipitate was collected by filtration, washed with water and purified by silica gel column chromatography (eluting solvent: chloform/methanol=30/1), to afford 2.1 g of Compound a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23][CH3:24])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23]([CH3:24])=[O:38])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
In DCM (5 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (150 mg, 0.35 mmol). m-CPBA (3-chloroperbenzoic acid, 110 mg, 0.64 mmol) was added at 0° C. The reaction was conducted for 30 min at ambient temperature. Then the reaction mixture was washed with water and extracted with DCM. The organic phase was dried, and the solvent was removed by rotary evaporation. Purification was performed by silica gel column chromatography (DCM/methanol=50/1) to give solid 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulphinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (100 mg, 64% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>C(#N)C>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCCN1CCCC1=O
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCCN1CCCC1=O
Yield: 52.5 %

Procedure:
250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser, and a CaCL2 drying tube. 452 mg (3.18 mmol) 1-(3-aminopropyl)-2-pyrrolidinone and 1 ml acetonitrile were added. The solution was heated to reflux for 17 hours at which time all of the acetonitrile was evaporated leaving a dark viscous oil. The oil was chromatographed on 15 g silica gel, eluting with 40% methanol/60% ethyl acetate. This procedure gave 185 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[3-(2-oxopyrrolidin-1-yl)propyl]propanamide (AIT-0034) as a pure white solid. Yield: 53%
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[N-]=C=O>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NNC(=O)C[C@H]1CCN(C(=O)C2CC2)C1
Agent: [N-]=C=O
Solvent: ClCCl
Product: O=C(C[C@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
In a round bottom flask under nitrogen, a solution of 2-[(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (2.16 mmol) in dichloromethane (5 mL) was cooled to 0° C. and 1-bromo-4-isocyanatobenzene (2.16 mmol) was added. Once the isocyanate dissolved, the cooling bath was removed and the reaction was allowed to warm to room temperature and was stirred for 3 h. The reaction was filtered to collect the white precipitate, washed with 10 mL cold dichloromethane, air dried for 1 h and then dried in a vacuum oven (60° C.) overnight to provide the title compound (88% yield). MS(ES)+ m/e 409.1, 411.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[Cl:29][CH2:30][C:31]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[C:6]([Cl:21])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12]1)=[O:32]
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)CCl)N=C2Cc1c(Cl)cncc1Cl
Temperature: 25 °C
Yield: 110.5 %

Procedure:
At room temperature, under N2 and stirring, a solution of 1-[4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1H-phthalazine (1.9 g, 5.9 mmoles), prepared as described in example 22, in dry THF (70 ml) was added with triethylamine (2.05 ml, 14.7 mmoles) and cooled at 0° C. Chloroacetyl chloride (0.56 ml, 7.07 mmoles) was dropwise added and a precipitate formed. After 1 night further 50% of triethylamine and chloroacetyl chloride was added, and after 20 hours at room temperature the mixture was poured into water/ice, concentrated and extracted more times with CH2Cl2. The organic phase was washed with water, anhydrified and brought to dryness to give 2.6 g of the title compound (quantitative yield).
Reaction SMILES: [C:1]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[CH2:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:1]([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1Cc2ccccc2C1
Yield: 69.1 %

Procedure:
Dissolve 2-(carboethoxy)indan (6.49 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 2-indancarboxylic acid as a tan solid (3.82 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[C:33]([F:40])=[CH:32][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[C:6]1=[O:31].Cl[C:42]1[N:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:43]1[CH:44]=[CH:45][CH:46]=[N:47][C:42]=1[C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([N:7]3[CH2:8][CH2:9][C@H:5]([O:4][C:3]4[CH:32]=[C:33]([F:40])[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:35][C:2]=4[F:1])[C:6]3=[O:31])[CH2:11][CH2:12]2)=[N:21][CH:20]=1
Reactant: Clc1ncccn1
Reactant: CC1(C)OB(c2cnc(N3CCC(N4CC[C@H](Oc5cc(F)c(S(C)(=O)=O)cc5F)C4=O)CC3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCN(C3CCN(c4ncc(-c5ncccn5)cn4)CC3)C2=O)cc1F
Temperature: 80 °C
Yield: 47.8 %

Procedure:
(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (173 mg, 0.299 mmol), 2-chloropyrimidine (41.1 mg, 0.359 mmol) and 2M Na2CO3 (748 μL, 1.50 mmol) were dissolved in dioxane (3 mL) and purged with nitrogen. Pd(PPh3)4 (34.6 mg, 0.0299 mmol) was added and the reaction was heated to 80° C. for 3 hours. The reaction was cooled to ambient temperature, partitioned between water and CH2Cl2, extracted twice, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (eluting with 90 to 100% EtOAc in hexanes) to afford (S)-1-(1-(2,5′-bipyrimidin-2′-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (76 mg, 0.143 mmol, 47.9% yield) as a white solid. Mass spectrum (apci) m/z=531.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6](O)=[O:7])[CH:4]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:7])[CH:4]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C(=O)O)nc2ccccc12
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Methoxyquinaldic acid (7.25 g) was dissolved in dry dimethylformamide (20 ml). N,N'-carbonyldiimidazole (5.8 g) was added, and the solution was stirred for 6 hours at room temperature. 5-Aminotetrazole (3.69 g) was added and the mixture was stirred overnight at room temperature. The solid was filtered off, washed with methanol and dissolved in dimethylformamide (500 ml) with the minimum addition of dimethylaminoethanol to effect dissolution. Water (50 ml) was added, and the solution was adjusted to pH 2 by the addition of aqueous hydrochloric acid. The solid was filtered off to give 4-methoxy-N(1H-tetrazol-5-yl)quinaldamide, m.p. 289° (d).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([CH3:12])[C:7]2=[O:13].CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:8]1[C:7](=[O:13])[C:6]2[C:11](=[C:2]([C:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH:26]=3)[CH:3]=[CH:4][C:5]=2[N+:14]([O-:16])=[O:15])[NH:10][CH:9]=1
Reactant: Cc1c[nH]c2c(Br)ccc([N+](=O)[O-])c2c1=O
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CC=C(c2ccc([N+](=O)[O-])c3c(=O)c(C)c[nH]c23)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 8-bromo-3-methyl-5-nitroquinolin-4(1H)-one (Compound 304E, 700 mg, 2.47 mmol), ethyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)cyclohex-3-enecarboxylate (1.8 g, 6.43 mmol, commercially available or can be prepared according to WO2008/099221), Pd(PPh3)4 (20 mg), and Na2CO3 (1 g, 9.43 mmol) in 1,4-dioxane/H2O (150 mL, 4:1) was evacuated and purged with N2. The reaction mixture was stirred at 100° C. for 18 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The material was purified by flash column chromatography to afford the desired compound (600 mg, yield: 67%). 1H NMR (DMSO-d6, 400 MHz): δ=1.22 (t, J=7.2 Hz, 3H), 1.85 (m, 1H), 1.96 (s, 3H), 2.08 (m, 1H), 2.26 (m, 1H), 2.38-2.49 (m, 3H), 2.78 (m, 1H), 4.12 (q, J=7.2 Hz, 2H), 5.84 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.83 (d, J=6.0 Hz, 1H), 10.94 (d, J=6.0 Hz, 1H).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12](Cl)(=[O:14])=[O:13].O>O1CCOCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12]([NH:2][CH3:1])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CN
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl

Procedure:
40% strength aq. methylamine soln. (36.0 g, 464 mmol) was added dropwise to a soln. of 2,4,6-trichorobenzenesulfonic acid chloride (10.0 g, 35.7 mmol) in 1,4-dioxane (60 ml) and the mixture was stirred at RT for 30 min. Water (500 ml) was then added, with vigorous stirring, whereupon a white precipitate formed, which was filtered out and dried over potassium hydroxide in a desiccator.