Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:31][CH2:30]2)[S:27][CH:28]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 35.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (212 mg, 0.782 mmol), 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 101 mg (35.2%) of the desired product as a solid. mp 215-216° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])(=[O:11])=[O:10].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1Br.C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])(=[O:11])=[O:10]
Reactant: Nc1ccccc1CS(=O)(=O)NCCOCCO
Reactant: Clc1cccc(Cl)c1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(Cc1ccccc1Nc1c(Cl)cccc1Cl)NCCOCCO
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(2-aminophenyl)-N-[2-(2-hydroxyethoxy)ethyl]-methanesulfonamide (100 mg, 0.37 mmol), 1,3-dichloro-2-bromobenzene (103 mg, 0.46 mmol), K2CO3 (126 mg, 0.99 mmol) and XantPhos (21 mg, 0.04 mmol) in 1,4-dioxane (2 ml) under nitrogen in a microwave tube was added Pd2dba3 (17 mg, 0.019 mmol) in one portion and the tube sealed. The reaction was heated with stirring in a microwave at 160° C. for 30 minutes. The reaction was cooled before filtering through celite. The crude reaction mixture was purified by column chromatography eluting with ethyl acetate:hexane to afford 1-[2-(2,6-Dichlorophenylamino)phenyl]-N-[2-(2-hydroxyethoxy)-ethyl]methanesulfonamide as product (50.5 mg, 33%); Rf (ethyl acetate:hexane 1:1) 0.11; δH (400 MHz, CDCl3) 7.34 (3H, m), 7.23 (1H, t), 7.19 (1H, s), 7.02 (2H, m), 6.60 (1H, d), 5.70 (1H, s), 4.56 (2H, s), 3.70 (2H, s), 3.56 (4H, m), 3.29 (2H, dt) and 2.83 (1H, s); LCMS Rt=3.97 min, m/z (ES+) 441 (M+Na).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[CH:12]1([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[CH:12]1([N:15]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]([C:3]2[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=2[F:1])=[O:10])[CH2:13][CH2:14]1
Reactant: c1ccc([C@H]2CCCC[C@H]2NC2CC2)cc1
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)N(C1CC1)[C@@H]1CCCC[C@@H]1c1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
At ambient temperature, a solution of 180 mg (1.02 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 200 mg (0.93 mmol) of cis-N-cyclopropyl-2-phenylcyclohexanamine and 100 mg (1.02 mmol) of triethylamine in 5 ml of tetrahydrofurane. The reaction mixture is stirred for 2 hrs at 70° C. The solvent is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×50 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and brine and dried over a Chemelut™ cartridge to yield after concentration 380 mg of a yellow oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 160 mg (46% yield) of cis-N-cyclopropyl-5-fluoro-1,3-dimethyl-N-(2-phenylcyclohexyl)-1H-pyrazole-4-carboxamide as a colorless oil (M+H=356).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=O)[C:3]=1[CH2:19][CH2:20][OH:21].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.C([O-])(O)=O.[Na+]>CS(O)(=O)=O>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2](=[O:1])[C:3]3[CH2:19][CH2:20][O:21][C:4]2=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(CCO)c(O)c2cccnc2n1-c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=c1c2c(n(-c3ccccc3)c3ncccc13)OCC2
Temperature: 70 °C

Procedure:
A solution of 4-hydroxy-3-(2-hydroxyethyl)-1-phenyl-1,8-naphthyridin-2 (1H) -one in Eaton's Reage P2O5 in methane sulfonic acid; 40 ml.) was stirred in an atmosphere of nitrogen and was heated to 70° C. for 2 hr. After cooling, the product was poured into water, adjusted to pH 4 with NaHCO3, filtered, washed with water, air dried and recrystallized from isopropanol with decolorization to yield the product, m.p. 245°-247° C.
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.CN(CCCCl)C.[CH3:12][C:13]1[CH:29]=[C:16]2[NH:17][C:18](=[O:28])[C:19]3[CH:24]=[N:23][C:22]4[NH:25][N:26]=[CH:27][C:21]=4[C:20]=3[N:15]2[N:14]=1.C(N1C2N=CC3C(=O)NC4N(N=C(C)C=4)C=3C=2C=N1)C>>[CH3:12][C:13]1[CH:29]=[C:16]2[N:17]([CH2:3][S:2][CH3:1])[C:18](=[O:28])[C:19]3[CH:24]=[N:23][C:22]4[NH:25][N:26]=[CH:27][C:21]=4[C:20]=3[N:15]2[N:14]=1
Reactant: CSCCl
Reactant: Cc1cc2[nH]c(=O)c3cnc4[nH]ncc4c3n2n1
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Agent: CN(C)CCCCl
Product: CSCn1c(=O)c2cnc3[nH]ncc3c2n2nc(C)cc12

Procedure:
By substituting methylthiomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 4 and substituting the 2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one obtained in Example 8 for the 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one, 2-methyl-4-methylthiomethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[OH:21])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.C(O)(=O)C.CCOCC>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH3:38])[CH2:17][C@H:16]2[OH:21])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC[C@H]2CCNC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@H]2CCN(C)C[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a stirred solution of (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-3-ol dihydrochloride (Example 35, ˜0.2 mmol) in dichloromethane (2.0 mL), was added formaldehyde solution in water (37%, 2.0 mmol, 0.2 mL), and 1 drop of acetic acid. Then sodium triacetoxyborohydride (2.0 mmol, 424 mg) was added. The mixture was stirred at room temperature for 0.5 hour, then condensed, worked up and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, condensed, triturated with hexanes to provide title compound (51 mg). LCMS: m/z 455 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.48 (1H, s), 7.39-7.43 (2H, m), 7.08-7.12 (2H, m), 4.52-4.59 (1H, m), 4.39-4.48 (2H, m), 4.27 (1H, bs), 3.38-3.54 (2H, m), 3.02-3.26 (4H, m), 2.85 (3H, s), 2.25-2.37 (1H, m), 1.78-2.07 (6H, m), 1.20-1.43 (10H, m), 0.81 (3H, t).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:11]([NH:19][C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N1C(=O)Cc2ccccc21)c1ccccc1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
To a stirred slurry of 399 mg (3.0 mmole) of 2-oxindole in 7 ml of toluene was added 485 mg (3.3 mmole) of benzoyl isocyanate. The mixture was heated under reflux for 2.2 hours and then it was cooled to room temperature. The solid was recovered by filtration and it was then dissolved in ca. 10 ml of hot acetonitrile. The acetonitrile solution was decolorized using activated carbon and then allowed to cool and the precipitate was recovered by filtration. Recrystallization of the precipitate from acetonitrile gave 131 mg of the title compound, mp 183.5°-184.5° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C@@:13]([CH3:20])([CH:15]([O:18][CH3:19])[O:16][CH3:17])[C@H:12]3[O:21][C@H:11]3[C:10]=2[CH:22]=1)(=[O:4])=[O:3].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[N:33]=[N:34][N:35]([CH3:37])[N:36]=2)=[CH:26][CH:25]=1>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C@@:13]([CH3:20])([CH:15]([O:16][CH3:17])[O:18][CH3:19])[C@@H:12]([OH:21])[C@H:11]([N:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:31][C:32]3[N:33]=[N:34][N:35]([CH3:37])[N:36]=3)[C:10]=2[CH:22]=1)(=[O:3])=[O:4]
Reactant: COC(OC)[C@]1(C)Oc2ccc(OS(C)(=O)=O)cc2[C@@H]2O[C@@H]21
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Product: COC(OC)[C@]1(C)Oc2ccc(OS(C)(=O)=O)cc2[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 26.8 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2R,3S,4S)-6-methane sulfonyloxy-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (231 mg, 0.70 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (187 mg, 0. 84 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:1), to give desired compound (104 mg, yield: 27%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:20])=[N:11][N:12]3[C:17](O)=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].O=P(Cl)(Cl)[Cl:30]>>[CH3:1][N:2]([CH3:21])[C:3]1[N:4]=[CH:5][C:6]([C:9]2[C:10]([CH3:20])=[N:11][N:12]3[C:17]([Cl:30])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:7][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(C)c(-c3ccc(N(C)C)nc3)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)n2nc(C)c(-c3ccc(N(C)C)nc3)c2n1

Procedure:
Intermediate 8 was dissolved in POCl3 (2 ml) and refluxed for 2 hours. The reaction mixture was cooled and poured onto ice. The solution was made basic (pH =9) by addition of solid sodium carbonate and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated, yielding 3-[6-(dimethylamino)-3-pyridinyl]-2,5-dimethyl-7-chloro-pyrazolo[2,3-a]pyrimidine (intermediate 9).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:3]4[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=4[Cl:1])=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A dry 25 mL flask was charged with 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (0.180 g, 0.873 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by rotary evaporation. The crude acid chloride dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature and the precipitate was filtered and washed with THF (˜5 mL) affording pure 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.233 g, 0.571 mmol, 72%).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)C.C(O)(=O)C.[NH2:34]N>ClCCl>[CH:28]1[CH:27]=[CH:26][N:18]2[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]4[NH:34][N:2]=[CH:4][N:5]=4)=[CH:8][CH:9]=3)=[O:14])[CH2:16][C:17]=12
Reactant: NN
Reactant: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(c1ccc(-c2ncn[nH]2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 42.4 %

Procedure:
A mixture of N-(dimethylaminomethylene)-4-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-carbonyl)-benzamide (1.0 g) from Example 46, glacial acetic acid (15 ml), and anhydrous hydrazine (0.16 g) was refluxed for 15 hours and the volatiles removed in vacuo. Saturated aqueous sodium bicarbonate solution was added and the resultant solid was recovered by filtration. The solid was refluxed for 4 hours and the volatiles removed in vacuo to give a solid. The solid was dissolved in dichloromethane and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.39 g), m.p. 225-227° C.; MS, m/z: 355 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH:19]=[N:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][C:22](/[CH:26]=[C:11]3/[C:12](=[O:16])[NH:13][C:14]4[C:10]/3=[CH:9][CH:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:15]=4)=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=C1Nc2cc(-c3cccnc3)ccc2/C1=C\c1ccc2[nH]ncc2c1

Procedure:
According to the method of Example A19, utilizing 6-(pyridin-3-yl)indolin-2-one (25 mg, 0.12 mmol) and 1H-indazole-5-carbaldehyde (17.4 mg, 0.12 mmol), the title compound was obtained as an orange solid (7 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.32 (br. s., 1H), 10.81 (s, 1H), 9.04 (s, 1H), 8.89 (d, J=1.26 Hz, 1H), 8.57 (dd, J=4.55, 1.26 Hz, 1H), 8.52 (d, J=7.83 Hz, 1H), 8.25 (s, 1H), 8.06-8.11 (m, 1H), 8.04 (s, 1H), 7.87 (d, J=7.83 Hz, 1H), 7.62 (d, J=8.84 Hz, 1H), 7.49 (dd, J=7.33, 4.55 Hz, 1H), 7.38 (dd, J=7.83, 1.26 Hz, 1H), 7.11 (d, J=1.01 Hz, 1H); MS ESI 339.1 (100) [M+H]+, calcd for [C21H14N4O+H]+ 339.4.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[O:15][CH3:16].CC1C=C(C2OC(C)=NN=2)C=CC=1C1C=CC(C(O)=O)=CC=1>>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1ccc([N+](=O)[O-])cc1N(CCN(C)C)C(=O)OC(C)(C)C
Agent: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Product: COc1ccc(N)cc1N(CCN(C)C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from N,N-dimethyl-N'-t-butyloxycarbonyl-N'-(2-methoxy-5-nitrophenyl)ethylenediamine (D20, 0.50 g, 0.0015 mol) using the method of Description 2 (0.37 g, 80%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and hexanoyl chloride (336.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:1). The fractions containing the 1-(4-benzylpiperazin-1-yl)hexan-1-one are collected and the solvent is removed in vacuo to give 453 mg of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:26]([CH3:27])[C:21]([O:20][CH3:19])=[C:22]([CH3:31])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1c(C)cc(B(O)O)cc1C
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(C)c(OC)c(C)c3)cccc2c1N
Yield: 83 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (125 mg, 0.40 mmol) and (4-methoxy-3,5-dimethylphenyl)boronic acid (144 mg, 0.80 mmol) were reacted to afford the title compound (121 mg, 82% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.57 (bs, 1H), 7.66-7.85 (m, 3H), 7.32 (s, 2 H), 3.78 (s, 3H), 3.46 (apparent q, J=6.6 Hz, 2H), 2.36 (s, 6H), 1.67 (apparent sextet, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, m/z=365 (M+H) HPLC 2.08 min.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH:41]2[CH2:46][CH2:45][C:44]3([CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH2:43][CH2:42]2)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH:41]3[CH2:42][CH2:43][C:44]4([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]4)[CH2:45][CH2:46]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CCC3(CCCCC3)CC2)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoate, the title compound was obtained as an orange oil (0.33 g, 79%): MS (ES+) m/z 403.1 (M+1).
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH3:17][O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:19][CH2:18][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1ncnc2c1CN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Product: COc1ncnc2c1CNCC2
Yield: 96.9 %

Procedure:
250 mL flask was charged with 6-benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (4.08 g, 16.0 mmol), 10% palladium on charcoal (400 mg) and methanol (100 mL). The reaction was evacuated and purged with hydrogen three times, and hydrogenated (1 atm) overnight. The mixture was filtered through a “Dry disk” membrane filter, and concentrated in vacuo to give an orange oil (2.56 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13](O)=[O:14])=[CH:9][N:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[OH-].[Na+]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][N:8]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCc1ccc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(pyrid-2-yl)-5-pyridine carboxylic acid (0.320 g, 1.60 mmol) in THF (5 mL) at 0° C. is added 1.0M lithium aluminum hydride in diethyl ether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction is allowed to stir at ambient temperature for 3 hours, cooled to 0° C., and water (0.10 mL), 4N aq. NaOH (0.10 mL), and water (0.30 mL) are added sequentially. The reaction is filtered through a pad of Celite and the filtrate is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1(C)C=CC=CC=1>C1CCCCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][S:10](=[O:12])(=[O:11])[NH2:13]
Reactant: Oc1ccccc1Cl
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1ccccc1Cl
Yield: 58.8 %

Procedure:
This compound was prepared by the procedure used in Example 75. A mixture of 12.8 g (0.1 mole) of 2-chlorophenol, 14.8 g (0.105 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 12.2 g (59%) of the title compound as a white solid, mp 62.5°-63.5° C. (cyclohexane-benzene).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:10]=1[C:11]#[N:12])=[O:7])(=O)C.N>CO>[OH:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:10]=1[C:11]#[N:12])=[O:7]
Reactant: COc1cccc(NC(=O)COC(C)=O)c1C#N
Agent: N
Solvent: CO
Product: COc1cccc(NC(=O)CO)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 2-(acetoxyacetylamino)-6-methoxybenzonitrile (2.5 g) in methanol (250 ml) is added dropwise 28%aqueous ammonia (5 ml). The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol to give the title compound (1.8 g) having the following physical properties.