Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:15]([CH2:16][CH3:17])=[N:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1.[OH-].[Na+]>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:14]=[C:15]([CH2:16][CH3:17])[C:6]1=[O:5]
Reactant: CCc1nc2c(nc1O)CCCC2
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CCc1nc2c(n(CCO)c1=O)CCCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-ethyl-5,6,7,8-tetrahydro quinoxaline (8.90 g, 50 mM) in dilute aqueous 5N NaOH (50 ml) and t-butanol (150 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. Water was added to the residue, which residue was then extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (100:1) to obtain compound 646 (9.30 g, yield: 83.8%).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[SH:24][CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C.Cl>COCCOCCOC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([S:24][CH2:25][C:26]([OH:28])=[O:27])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: O=C(O)CS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: O=C(O)CSc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide (0.40 g, 1.05 mmol), mercaptoacetic acid (0.11 mL, 1.60 mmol), triethylamine (0.59 mL, 4.2 mmol) in diglyme (2.5 mL) was heated with stirring at 130° C. under an atmosphere of nitrogen for 18 hours. The product mixture was treated with 1 M aq HCl at 0° C. The resulting yellow solid was filtered, washed with diethyl ether to provide the title acid.
Reaction SMILES: C(O[CH:4]([O:25]CC)[C:5]#[C:6][C:7]([CH:15]([CH3:24])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)O)C.C(=O)(O)[O-:29].[Na+]>S(=O)(=O)(O)O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH:15]([C:7]1([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6](=[O:29])[CH:5]=[CH:4][O:25]1)[CH3:24]
Reactant: O=C([O-])O
Reactant: CCOC(C#CC(O)(c1cccnc1)C(C)c1ccc(Cl)cc1Cl)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(c1ccc(Cl)cc1Cl)C1(c2cccnc2)OC=CC1=O
Temperature: 25 °C

Procedure:
A solution of 1 g of α-(3,3-diethoxy-1-propynyl)-α-(2,4-dichloro-α-methylbenzyl)-3-pyridinemethanol in 30 ml of 4N sulphuric acid is heated at 120° C. for 1.5 hours while stirring and the reaction mixture is subsequently left to cool to room temperature, neutralized with solid sodium bicarbonate and extracted with methylene chloride. The organic phase is washed three times with saturated aqueous sodium chloride solution and evaporated under reduced pressure. Thereafter, the residue is subjected to a column chromatography on silica gel using methylene chloride/ethyl acetate (4:1) as the eluent and it is recrystallized from n-hexane. In this manner there is obtained 0.4 g of 2-(2,4-dichloro-α-methylbenzyl)-2-(3-pyridyl)-3(2H)-furanone, m.p. 111°-111.5° C.
Reaction SMILES: O1CCC(N2C=C([C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:19]=4)[CH:15]=[N:16][CH:17]=3)C=N2)CC1.[C:31]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:19]=4)[CH:15]=[N:16][CH:17]=3)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: Nc1cc(-c2cncc(-c3cnn(C4CCOCC4)c3)c2)cc(-c2ccccn2)n1
Product: CC(C)(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(N)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
This compound is prepared analogously to 5″-[1-(Tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-[2,2′;4′,3″]terpyridin-6′-ylamine (Example 2.156) by replacing 1-(tetrahydro-pyran-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Intermediate B18) with 4-((4-tert-butylpiperazin-1-yl)methyl)phenylboronic acid (Intermediate B10).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[CH:19]=[C:18]([S:20][CH3:21])[N:17]=[CH:16][N:15]=1>CN(C=O)C.C(OCC)(=O)C.O>[CH3:21][S:20][C:18]1[CH:19]=[C:14]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:15]=[CH:16][N:17]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CSc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 4-nitrophenol (8.04 g, 58 mmol) in DMF (36 ml) is added at 0° C. sodium hydride (2.5 g, 63 mmol, 60% in mineral oil) and stirring is continued for 30 minutes at r.t. A solution of 4-chloro-6-methylsulfanyl-pyrimidine (8.44 g, 52.5 mmol) in DMF (12 ml) is added and the reaction mixture is sealed in a reaction tube and heated in the microwave to 130° C. for 20 minutes. The reaction mixture is taken up in ethyl acetate and water. The organic phase is washed dried and evaporated. Recrystallization from ethyl acetate results in 6.08 g (44%) of an off-white powder of sufficient purity.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:33]=[CH:32][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[O:14])=[C:11]([N+:34]([O-])=O)[CH:10]=2)[CH2:4][CH2:3]1.C(O)C.[Sn](Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.O1CCCC1>[NH2:34][C:11]1[CH:10]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:33]=[CH:32][C:12]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:21][CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:14]
Reactant: CN1CCN(Cc2ccc(C(=O)NCCCCN3CC=C(c4ccccc4)CC3)c([N+](=O)[O-])c2)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(Cc2ccc(C(=O)NCCCCN3CC=C(c4ccccc4)CC3)c(N)c2)CC1
Yield: 126.8 %

Procedure:
To a stirred mixture of 4-(4-methylpiperazin-1-ylmethyl)-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.21 g), ethanol (5 ml) and dry tetrahydrofuran (10 ml) was added tin (II) chloride (0.33 g) and the mixture was refluxed for 1 hour. After cooling, chloroform (15 ml) and 1N sodium hydroxide (25 ml) were added and the mixture was stirred. The organic layer was separated and the remained aqueous layer was extracted with chloroform. The organic layer and extract were combined and dried over magnesium sulfate and evaporated to give 2-amino-4-(4-methylpiperazin-1-ylmethyl)-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin 1-yl)butyl]benzamide (0.25 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[CH3:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[CH3:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(F)c(-c4ccc(Cl)cc4C)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccc(Cl)cc4C)c3O2)cc1
Yield: 99.5 %

Procedure:
Treatment of ((2R)-8-(4-chloro-2-methylphenyl)-7-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.09 mmol) with platinum (IV) oxide (84% Pt, 0.21 g) in ethanol (25 mL) and ethyl acetate (5 mL) according to the procedure described for Example 69, Step 8 provided 0.5 g (100%) of ((2R)-8-(4-chloro-2-methylphenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate as a light brown oil.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@H:9]([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1([CH3:12])[CH3:11])=[O:3].[CH3:13][CH2:14]O>>[CH3:12][C:5]1([CH3:11])[CH2:6][CH2:7][CH2:8][C@@H:9]([CH3:10])[C@@H:4]1[C:2](=[O:3])[CH:1]=[CH:13][CH3:14]
Reactant: CCO
Reactant: CC(=O)[C@H]1[C@H](C)CCCC1(C)C
Product: CC=CC(=O)[C@H]1[C@H](C)CCCC1(C)C

Procedure:
The reaction was carried out in exactly the same manner as Reference Example 6 using 37 g of the (1S,6R)-2,2,6-trimethylcyclohexyl methyl ketone (1a) synthesized in Example 2 to obtain 29 g of (1S,6R)-1-(2,2,6-trimethylcyclohexyl)-2-buten-1-one (10a) (b.p.: 73-75° C./19.95 Pa (0.15 torr), [α]D=+15.52° (c 1.00, EtOH, 24° C.).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[O:6]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[CH:16]=[C:15]([C:36]([OH:38])=O)[CH2:14][CH2:13]2)=[CH:7]1.S(Cl)(Cl)=O>O1CCCC1>[O:6]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[CH:16]=[C:15]([C:36]([NH:12][C:18]3[CH:19]=[CH:20][C:21]([CH2:4][N:2]([CH3:1])[CH:3]4[CH2:9][CH2:10][O:6][CH2:7][CH2:8]4)=[CH:22][CH:17]=3)=[O:38])[CH2:14][CH2:13]2)=[CH:7]1
Reactant: CN(C)C=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccoc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (159 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (118 mg) and triethylamine (546 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1 8), which was recrystallized from hexane-ethyl acetate to give 1-(3-furylmethyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 61) (153 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C:2](=[O:31])[CH:3]([OH:30])[CH:4]([NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:17]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:18]1)[CH2:5][CH2:6][CH2:7][CH3:8]>C(OCC)(=O)C>[NH2:1][C:2](=[O:31])[C:3](=[O:30])[CH:4]([NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:17]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:18]1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(NC(=O)c1cccnc1-n1ccc(CN2CCCCC2)n1)C(O)C(N)=O
Solvent: CCOC(C)=O
Product: CCCCC(NC(=O)c1cccnc1-n1ccc(CN2CCCCC2)n1)C(=O)C(N)=O

Procedure:
Oxidation of N-(1-amino-2-hydroxy-1-oxoheptan-3-yl)-2-(3-(piperidin-1-ylmethyl)-1H-pyrazol-1-yl)nicotinamide (180 mg, 0.378 mmol) as described in example 1.4 and treatment of the crude product with a mixture of ethyl acetate and MTB 1:1, filtering off the remaining solid and drying gave the title compound as white amorphous solid; 63 mg, ESI-MS [M+H]+: 427.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.67 (d, 1H), 8.51 (m, 1H), 8.33 (m, 1H), 7.99 (m, 1H), 7.82 (m, 1H), 7.75 (m, 1H), 7.44 (m, 1H), 6.40 (m, 1H), 5.07 (m, 1H), 3.40 (s, 2H), 2.33 (m, 4H), 1.76 (m, 1H), 1.48 (m, 5H), 1.36 (m, 6H), 0.87 (m, 3H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:30])=[C:27]([CH:29]=1)[NH2:28]>>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:28][C:27]3[CH:29]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=3[CH3:30])=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1ccc(Cl)cc1N
Product: Cc1ccc(Cl)cc1Nc1ncc(C(=O)NCC2CCCCC2)c(C(F)(F)F)n1
Yield: 54.3 %

Procedure:
In a manner similar to Example 243, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-ioxan (1 ml) and 5-chloro-2-methyl aniline (Aldrich) (110 mg) were reacted to give the title compound (36 mg)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:8]([CH3:10])=[O:9])[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:14])(=O)=O>C(Cl)Cl>[Cl:14][CH2:10][C:8](=[O:9])[C:3](=[N:2][OH:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=NO)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=NO)C(=O)CCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.9 %

Procedure:
In 50 ml of methylene chloride is dissolved 19 g of methyl 2-hydroxyiminoacetoacetate and under ice-cooling and stirring 19.6 g of sulfuryl chloride is added dropwise. The mixture is stirred at room temperature for 3 days, after which the methylene chloride is distilled off under reduced pressure. The residue is dissolved in 200 ml of ether and washed seven times with 100 ml portions of water. The ether layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 20.2 g of methyl 4-chloro-2-hydroxyiminoacetoacetate as a light-yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a solution of ethyl [4-({(2-methoxyethyl)[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (90 mg, 0.18 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), was added 2M NaOH aq. (1 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue diluted with water (10 mL) acidified with 2M HCl, before extraction into ethyl acetate (2×20 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a white solid (28 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][NH:10][C:9]3=O)[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:19])=O>CN(C=O)C>[Cl:19][C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=c1[nH]cnc2ccc(-n3ccnc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(-n3ccnc3)cc12

Procedure:
6-(1-Imidazolyl)-3,4-dihydroquinazolin-4-one (1.0 g) was dissolved in phosphorus oxychloride (15 ml). DMF (2 drops) was added and the mixture was heated at reflux for 1 hour. The mixture was evaporated, the residue was dissolved in methylene chloride, washed with sodium bicarbonate solution and the organic layer was dried (MgSO4) and evaporated to give 4-chloro-6-(1-imidazolyl)quinazoline (0.36 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:19]1([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1
Reactant: C[Si](C)(C)CCOCn1ncc2ccc(Br)cc21
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ncc2ccc(C3CC3)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A round-bottomed flask was charged with 6-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (0.80 g, 2.44 mmol), cyclopropylboronic acid (377 mg, 4.39 mmol), palladium(II) acetate (28 mg, 0.125 mmol), potassium phosphate tribasic (1.04 g, 4.88 mmol), toluene (9 ml) and water (0.9 ml). The reaction mixture was stirred at 100° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-5% EtOAc) to afford 670 mg (90%) of 6-cyclopropyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a light yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (55 mg, 0.12 mmol), β-alanine (863 mg, 9.7 mmol) and NaOMe solution (14.5 mL, 7.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 46 mg of the title compound. MS: (+) m/z 512.27 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:11][C@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@H:12]([NH:11][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[O:3][C:4]=3[CH3:10])=[O:9])[CH3:28])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c(C)o1
Yield: 54.7 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,5-dimethyloxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2,5-dimethyl-1,3-oxazole-4-carboxylic acid (0.254 g, 1.749 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.457 mmol). The product was triturated using diethyl ether. Yield 54.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.08 (d, 3H), 2.43 (d, 6H), 4.28 (dd, 1H), 4.34-4.45 (m, 2H), 6.96 (d, 1H), 7.83 (d, 1H), 7.96-8.01 (m, 2H), 8.10 (dd, 1H), 8.23 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=427.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-methoxybenzene-1-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)[S:5][C:6]=1[C:7]#[N:8].[F-:26].[Cs+]>CS(C)=O.CCOC(C)=O>[C:7]([C:6]1[S:5][C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:3][C:2]=1[F:26])#[N:8]
Reactant: [F-]
Reactant: CC(C)n1cc(-c2cc(Cl)c(C#N)s2)c2ccc(NS(C)(=O)=O)cc21
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)n1cc(-c2cc(F)c(C#N)s2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 21 °C
Yield: 3.5 %

Procedure:
Heat a mixture of N-[3-(4-Chloro-5-cyano-thiophen-2-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (Example 118) (0.15 g, 0.381 mmol) and CsF (0.324 g, 2.13 mmol) in DMSO (5 ml) at 150° C. for 6 hours under N2. Cool the mixture to 21° C. and dilute with EtOAc. Wash the mixture with water, brine, and dried over MgSO4. Filter the material and concentrate to dryness. Purify the crude product by reverse phase chromatography to yield 5 mg of the title compound. MS: 378.0 (MH+)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1>C1(C)C(C)=CC=CC=1>[CH2:18]([N:17]1[C:2]2[N:3]=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[CH:6][C:7]=2[C:8](=[O:9])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]1=2)[CH3:19]
Reactant: CCNc1ncccc1NC(=O)c1cc([N+](=O)[O-])cnc1Cl
Solvent: Cc1ccccc1C
Product: CCN1c2ncccc2NC(=O)c2cc([N+](=O)[O-])cnc21
Yield: 58.3 %

Procedure:
A solution of 1.80 g of 2-chloro-N-(2-ethylamino-3-pyridinyl)-5-nitro-3-pyridinecarboxamide in 25 ml of xylene was refluxed for four hours. After concentrating in vacuo, the residue was purified on a silical gel column eluting with 50% ethyl acetate/hexane to give 0.93 g of the title compound.