Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.N12CCCN=C1CCCCC2.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]2[C:44]([F:45])=[CH:43][C:33]([C:34]([NH:36][C@@H:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])=[O:35])=[C:32]([F:46])[CH:31]=2)[CH2:27]1)#[N:24]>C(O)(C)C>[Br:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:5]([C:26]2([CH2:25][C:23]#[N:24])[CH2:29][N:28]([C:30]3[CH:31]=[C:32]([F:46])[C:33]([C:34]([NH:36][C@@H:37]([CH3:42])[C:38]([F:39])([F:41])[F:40])=[O:35])=[CH:43][C:44]=3[F:45])[CH2:27]2)[CH:6]=1
Reactant: CCOC(=O)c1n[nH]cc1Br
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(=CC#N)C2)cc1F)C(F)(F)F
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1nn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)cc1Br
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a microwave vial was added isopropyl alcohol (10 mL), ethyl 4-bromo-1H-pyrazole-3-carboxylate (from ChemBridge) (788 mg, 3.60 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (48.9 μL, 0.327 mmol) and 4-[3-(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (from Example 4 step 4, 1.13 g, 3.27 mmol). The reaction mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified with flash chromatography (eluting with 0-35% ethyl acetate in hexanes) to give the desired product as white foam. 1H NMR (500 MHz, DMSO) δ 8.61 (s, 1H), 8.47 (d, J=8.7 Hz, 1H), 7.34 (dd, J=12.5 and 6.3 Hz, 1H), 6.62 (dd, J=11.9 and 7.3 Hz, 1H), 4.76 (dt, J=15.5 and 7.8 Hz, 1H), 4.61 (d, J=9.2 Hz, 2H), 4.39 (d, J=8.0 Hz, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.31 (m, 6H) ppm. LCMS calculated for C21H20BrF5N5O3 (M+H)+: m/z=564.1. Found: 563.8.
Reaction SMILES: [CH:1]1([NH:6][C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20](=O)[CH2:21][CH3:22].[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]([C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCCC1)CO2
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCN(C1CCCC1)[C@H]1COc2c(F)ccc(OC)c2C1
Reaction time: 8 h
Yield: 97 %

Procedure:
To the solution of (R)-3-(N-cyclopentylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran in methanol (25mL) were propanal (2 g, 36 mmol) and NaCNBH3 (2 g, 40 mmol) added. The solution was stirred overnight to give the desired compound in a 97% yield according to GC. The solvent was removed in vacuo and the residue was worked up by extraction to give 3.7 g of the title compound as a colorless oil. GC/MS (70 eV) M=307 (40% ).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH3:10][CH2:9][CH2:8][CH:2]([P:14]([O:15][CH2:16][CH3:17])([O:13][CH2:11][CH3:12])=[O:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC(Br)C(=O)OCC
Reactant: CCOP(OCC)OCC
Product: CCCC(C(=O)OCC)P(=O)(OCC)OCC

Procedure:
In analogy to the procedure given in Example 3: Ethyl 2-bromovalerate was treated with triethylphosphite to give triethyl 2-phosphonovalerate as a colorless clear liquid, b.p.=95°-110° C. (0.175 mm of Hg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH2:23])=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O>[NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:37]([C:36]2[CH:35]=[CH:34][C:33]([CH2:32][NH:31][C:29](=[O:30])[O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:41][CH:40]=2)=[O:38])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carbohydrazide (100 mg, 0.2833 mmol) and 4-[(tert-butoxycarbonylamino)methyl]benzoic acid (71.19 mg, 0.2833 mmol) in dmf (1.000 mL) was treated with triethylamine (28.67 mg, 39.49 μL, 0.2833 mmol) followed by TBTU (109.2 mg, 0.3400 mmol) and the resulting solution stirred at room temperature overnight. The solution was poured dropwise onto rapidly stirred water (15 ml), stirred at room temperature for 1 h and then filtered to give the product as a pale yellow solid which was dried under high vacuum at 83° C. and then used directly in the next step without further purification (136 mg, 84%)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[C@@H:19]1([NH:29][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:18])([F:17])[F:1])=[CH:10][CH:11]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
2′-(Trifluoromethyl)[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)=[O:11].[CH2:22]([NH2:25])[CH2:23][CH3:24].O>O1CCCC1>[CH2:22]([NH:25][C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:17][CH:16]=1)[CH2:23][CH3:24]
Reactant: CCCN
Reactant: O=C(O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
1.5 g of 4-(2,3-dichlorophenylcarbamoyl)phenyl acetic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 0.75 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.27 g of n-propylamine was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of water. The resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from benzene-hexane to obtain 1.5 g of desired N-n-propyl-4-(2,3-dichlorophenylcarbamoyl)phenylacetamide. The yield was 88.8%, and the melting point of this compound was from 177° to 178° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:18])[NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1Br)[CH2:2]2.[F:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].[ClH:36].CCOC(C)=O>O.CCOC(C)=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.CCO.O1CCOCC1>[ClH:36].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:13]2[S:14][CH:15]=[CH:16][C:12]=2[NH:11][C:10](=[O:18])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[CH:22][CH:21]=1
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: O=C(Nc1ccsc1Br)OC1CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(Nc1ccsc1-c1ccc(F)cc1)OC1CN2CCC1CC2
Temperature: 90 °C

Procedure:
A solution of a mixture of 1-azabicyclo[2.2.2]oct-3-yl(2-bromo-3-thienyl)carbamate (295 mg), Pd(PPh3)4 (103 mg), 4-fluorophenyl boric acid (187 mg), and 1,4-dioxane (3 mL) was added a 2 M aqueous Na2CO3 solution (0.89 mL), followed by stirring under heating at 90° C. for 5 hours. The reaction mixture was diluted with water, and extracted with EtOAc. The organic layer was washed with water, and adjusted into pH=1 with 1 M hydrochloric acid. Next, the aqueous layer was washed with EtOAc and adjusted to pH=10 with an aqueous NaOH solution, and the aqueous layer was extracted with CHCl3. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd., YAMAZEN YFLC WPrep2XY, CHCl3). The collected fraction was concentrated under reduced pressure and the oil obtained was dissolved in EtOAc, followed by addition of 4 M HCl/EtOAc, concentration under reduced pressure, and solidification to dry. To the residue obtained were added EtOH and EtOAc for crystallization to obtain 1-azabicyclo[2.2.2]oct-3-yl [2-(4-fluorophenyl)-3-thienyl]carbamate hydrochloride (135 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17](Cl)(=[O:19])=[O:18])[C:8]=2[S:9][CH:10]=1)[CH3:2].[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17]([N:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][N:28]=4)[CH2:31][CH2:32]3)(=[O:19])=[O:18])[C:8]=2[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2c(S(=O)(=O)Cl)c(OC)ccc12
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1csc2c(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c(OC)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
To a solution of compound from step 3 (50 mg, 0.14 mmol) in THF (2 mL) was added 1-[5-(trifluoromethyl)-2-pyridinyl]piperazine (32 mg, 0.14 mmol), followed by triethylamine (39 μL, 0.28 mmol). The reaction solution was stirred for 4 hours at room temperature. The solvent was evaporated and the residues were purified by silica gel chromatography to afford 22 mg of desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10](C)[C:11](N)=S>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([OH:21])([CH2:10][CH3:11])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Solvent: CCO
Product: CCC(O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 135.9 %

Procedure:
To a solution of (2R,3R)-3-(2,5-difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyramide (106 g, 340 mmol) in EtOH (500 mL) warmed at 50° C. in a water-bath was added 4-cyano-2′-bromoacetophenone (78.4 g, 350 mmol) portionwise over a period of 15 min and the mixture was stirred for 2 h at 50° C. After evaporation of EtOH under reduced pressure, the residue was dissolved in EtOAc (1.2 L) and the solution was washed with sat. NaHCO3 and brine, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography followed by trituration with t-BuOMe to give pure (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol (117 g, 79%) as a white powdery crystal.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18](O)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.Cl.[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:32])[CH3:31]>ClCCl>[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:18]([C:10]2[N:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:19])[CH2:35][CH2:34]1)([CH3:32])[CH3:31]
Reactant: CC(C)N1CCC(N)CC1
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)O)cc2ccccc21
Agent: CCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g 1-tert.-butoxycarbonylmethyl-1H-indole-2-carboxylic acid and 0.91 ml N-ethylmorpholine in 3 ml dichloromethane 0.6 g O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate were added and the mixture was stirred for 30 min at room temperature. 0.39 g 1-isopropyl-piperidin-4-ylamine hydrochloride were added to the mixture and the reaction mixture was further stirred for 1 hour. After removal of the solvent under reduced pressure the residue was partitioned between 15 ml water and 15 ml dichloromethane. The organic layer was washed with additional water and then dried over sodium sulphate. After filtration the solvent was removed under reduced pressure and a white solid was obtained. The residue was directly subjected to the subsequent reaction without further purification.
Reaction SMILES: [BH4-].[Na+].[O:3]=[CH:4][CH2:5][O:6][C:7]1([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1>>[OH:3][CH2:4][CH2:5][O:6][C:7]1([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC=O)(c2cccnc2)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(OCCO)(c2cccnc2)CC1
Yield: 70 %

Procedure:
Using NaBH4 reduction conditions, tert-butyl 4-(2-oxoethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate (2 g, 6.3 mmol) was reduced to give tert-butyl 4-(2-hydroxyethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate. The crude product was filtered over silica gel. Yield: 70%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C.CS(C)=O.CO.CO>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([C:5]4[CH:4]=[C:3]([NH:2][CH3:1])[CH:8]=[CH:7][N:6]=4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CNc1ccnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CO
Product: CNc1ccnc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 4-(methylamino)pyridine-2-carboxylic acid (61 mg, 0.40 mmol, available from Zerenex Molecular Ltd) in DMF (2 ml) was added HATU (150 mg, 0.40 mmol) and DIPEA (0.211 ml, 1.21 mmol). The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the mixture stirred at room temperature for 18 h. The reaction mixture was added to the top of a 10 g aminopropyl cartridge that had been pre-conditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The solvent was removed in vacuo to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (17 mg) as a cream solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:36]=[CH:35][C:9]2[N:10]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C>C(O)C>[CH:29]1([N:10]2[C:9]3[CH:35]=[CH:36][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16]3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3ncc(-c4ccccc4)nc3c1)n2C1CCCCC1
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3ncc(-c4ccccc4)nc3c1)n2C1CCCCC1
Yield: 81 %

Procedure:
To the solution of Compound 42 (0.95 mmol) in 25 mL ethanol 5 mL, 1 M NaOH was added and the mixture was refluxed for 1 h. It was then cooled and evaporated to dryness. The residue was dissolved in 50 mL water, acidified with 1M HCl to pH 4. The precipitate was filtered off, washed with water (4×) and dried to give 345 mg (81%) of the title compound which maybe further purified by RP-HPLC.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=1.O>CC(N(C)C)=O>[I:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][CH:9]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1CCNC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Ic1ccc(N2CCCC2)nc1
Temperature: 120 °C

Procedure:
Pyrrolidine (1.74 ml) was added to 2-chloro-5-iodopyridine (1 g) in dimethylacetamide (5 ml) and the solution heated at 120° C. for 4 h. After cooling, the reaction mixture was poured into water (60 ml) and the solid precipitate collected by filtration. Recrystallisation from ethyl acetate gave the product as off-white needles (0.33 g); the remaining material was adsorbed onto silica and purified by column chromatography eluting with 0 to 3% ethyl acetate in hexane to give a white solid (0.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:21]=3[N:20]([CH3:22])[CH2:19][CH2:18][CH2:17]4)[NH:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([S:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:21]=3[N:20]([CH3:22])[CH2:19][CH2:18][CH2:17]4)=[O:33])[NH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(SCc3cccc4c3N(C)CCC4)[nH]c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2nc(S(=O)Cc3cccc4c3N(C)CCC4)[nH]c2c1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 8-(5-methoxy-2-benzimidazolyl)thiomethyl-1-methyl-1,2,3,4-tetrahydroquinoline (0.80 g) in dichloromethane (30 ml) was added a solution of m-chloroperbenzoic acid (80%, 0.51 g) in dichloromethane (10 ml) by use of a pipet at -60° C. The mixture was stirred for 30 minutes at the same temperature. Aqueous sodium carbonate was added to the reaction mixture and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:ethyl acetate-n-hexane (2:3)] and recrystallized from ethyl acetate to give 8-(5-methoxy-2-benzimidazolyl)sulfinylmethyl-1-methyl-1,2,3,4-tetrahydroquinoline (0.38 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:22][CH2:23]CN=C=NCC.C(O)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[C:11]([OH:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c(O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1O
Temperature: 25 °C

Procedure:
A mixture of 1.2 g of 4-(t-butoxycarbonylamino)-2-hydroxybenzoic acid, 900 mg of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC·HCl), 550 mg of 4-dimethylaminopyridine, 1 ml of ethanol and 30 ml of dichloromethane was stirred at room temperature. The reaction mixture was treated with dichloromethane as the extracting solvent in an ordinary manner and then purified by the silica gel chromatography (ethyl acetate/hexane) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=[O:14])[C:11]([CH3:13])=O>>[CH2:20]([CH:17]([CH2:18][CH3:19])[CH2:16][O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH3:21]
Reactant: CCC(CC)COC(=O)C(C)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCC(CC)COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and 2-ethylbutyl pyruvate (prepared by following General Procedure AO above using 2-ethylbutanol (Aldrich) in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].CCN(C(C)C)C(C)C.[O:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1>CN1C(=O)CCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:40][CH2:39][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: NCC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2c(NCC3CCOCC3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 120 °C
Yield: 54.1 %

Procedure:
4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (1.890 g, 5.70 mmol) was dissolved in NMP (5 ml), DIPEA (2.487 ml, 14.24 mmol) was added followed by (tetrahydro-2H-pyran-4-yl)methanamine (0.82 g, 7.12 mmol) and the mixture was heated at 120° C. for 3 h, then cooled and the brown solution loaded onto a 70 g SCX-2 cartridge, the column washed with methanol (200 ml) and then eluted with 2M methanolic ammonia (100 ml) and methanol (100 ml). The eluant was evaporated in vacuo to give a brown solid. This was triturated with EtOAc (30 ml) and the solid collected by filtration to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-quinolinecarboxamide (1.58 g, 3.85 mmol, 54.1% yield) as brown solid. LCMS (formate) Rt 0.64, MH+ 411
Reaction SMILES: I[CH2:2][C:3]1[N:4]([CH3:16])[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:8]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].O>CN(C)C=O>[CH3:16][N:4]1[C:5](=[O:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:8]=[C:3]1[CH2:2][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1c(CI)nc(-c2ccncn2)cc1=O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(CN2C(=O)c3ccccc3C2=O)nc(-c2ccncn2)cc1=O
Temperature: 130 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a solution of 14.80 g (45.11 mmol) of 2-iodomethyl-1-methyl-1H-[4,4′]bipyrimidinyl-6-one in 30 ml of anhydrous dimethylformamide was added 16.71 g (90.21 mmol) of potassium phthalimide. The resulting mixture was stirred at 130° C. for 3 h. After cooling, water was added and the resulting mixture was stirred for 12 h at 0° C. The precipitate was filtered, heated in ethyl acetate and the precipitate was filtered. The product was dried to give 5.3 g (30%) of pure compound as a brown solid.