Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([C:34]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:35][CH2:36][CH2:37][NH2:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13][NH:38][CH2:37][CH2:36][S:35][C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Dissolve N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide (5.4 g, 13.8 mmol) and 2-[(triphenylmethyl)thio]ethylamine (4.4 g, 13.8 mmol) in 100 mL dichloromethane, then add triethylamine (3.0 mL, 20.8 mmol) into the solution, heat and reflux for 48 hours. After being cooled, wash with 100 mL sodium bicarbonate aqueous solution (NaHCO3) and take the organic layer. After being dried with anhydrous sodium sulfate and concentrated, liquid chromatography (silicon dioxide, ethyl acetate hexane=1:1) is used for separation and purification so as to get light yellow oil product
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C[O:7][C:8]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N+:20]=3[CH:21]=[C:12]2[CH:11]=[CH:10][CH:9]=1.Cl([O-])(=O)(=O)=O.[Na+]>Br>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:7][C:8]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N+:20]=3[CH:21]=[C:12]2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2c[n+]3ccccc3cc12
Agent: Br
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Oc1cccc2c[n+]3ccccc3cc12
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4 g of 10-methoxybenzo[b]quinolizinium perchlorate in 50 mL of 48% HBr was heated at 100° C. for 20 h, cooled to room temperature, and the resulting mixture was poured into 100 mL of 50% sodium perchlorate solution and stirred for 5 min. The precipitate was filtered, washed with ice-water, ether, ethyl acetate and air dried to afford 2.9 g of 10-hydroxybenzo[b]quinolizinium perchlorate, (Formula II: R1 =R2 =H;R7 =10-OH; X- =ClO4-) m.p. 218°-229° C.(d).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)=O)[CH3:2].[C:21]1([CH:28]=CC=[C:24](O)[CH:23]=1)[OH:22].P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[OH:22][C:21]1[CH:28]=[C:1]2[C:2]([C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=4)[CH:9]=3)=[CH:5][C:4](=[O:20])[O:3]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(=O)c1ccc2cc(OC)ccc2c1
Reactant: Oc1cccc(O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2cc(-c3cc(=O)oc4cc(O)ccc34)ccc2c1
Temperature: 0 °C
Yield: 68.8 %

Procedure:
A stirred solution of ethyl(6-methoxy-2-naphthoyl)acetate (36 g, 0.132 mole), resorcinol (14.6 g, 0.132 mole) and phosphoryl chloride (32 ml) in benzene (200 ml) was refluxed for 3 hours. The reaction mixture was allowed to cool, poured into ice/water and filtered to give the crude product as a red solid. Recrystallisation from ethanol gave 7-hydroxy-4(6-methoxy-2-naphthyl)coumarin (28.9 g, 69%) m.p. 223°-225° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[C:12]([CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10](F)[C:9]=2[CH3:20])[CH2:4][CH2:3]1.[F-].[K+].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([CH3:20])=[C:10]([C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH3:15])[C:13]=2[F:14])[NH:26][CH:23]2[CH2:25][CH2:24]2)[CH2:4][CH2:3]1
Reactant: Cc1c(F)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1
Reactant: NC1CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(NC2CC2)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1
Temperature: 100 °C
Reaction time: 23 h

Procedure:
To 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-methyl-5-nitrotoluene (1.73 g) are added anhydrous dimethyl sulfoxide (18 ml), potassium fluoride (0.53 g) and cyclopropylamine (2.2 ml) and the mixture is stirred at 100° C. for 23 hours. After cooling, the mixture is poured into ice-water, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane: methanol=40:1) to give 3-(4-methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6-nitro-N-cyclopropylaniline (1.65 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[O:23]=[CH:24][CH2:25][C:26](O)=[O:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[C:26]([OH:27])[CH2:25][CH:24]=[O:23]
Reactant: O=CCC(=O)O
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: CC1=C(CCON=C(O)CC=O)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-oxopropionic acid by the method of Example 1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:32])([O:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:33])[N:17]=2)[CH2:9]1.[OH:35][C:36]1([C:43]2[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1>>[OH:35][C:36]1([C:43]2[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[CH2:37][CH2:38][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:32])([O:30][CH3:31])[C:26]([F:29])([F:27])[F:28])[CH:23]=4)[N:18]([CH3:33])[N:17]=3)[CH2:11]2)[CH2:40][CH2:41]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: COC(F)(c1ccc2c(c1)c(NCC(=O)NC1CNC1)nn2C)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(OC)C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]2[NH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[N+:1]([C:4]1[CH:28]=[CH:27][C:7]2[NH:8][C:9]([S:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:40])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Sc2nc3cc([N+](=O)[O-])ccc3[nH]2)c(-c2ccccn2)c1
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(S(=O)c2nc3cc([N+](=O)[O-])ccc3[nH]2)c(-c2ccccn2)c1
Reaction time: 0.5 h

Procedure:
A solution of the sulphide of step (a) above (1.15 mmoles) in methanol (70 ml)/dichloromethane (50 ml) was stirred at 10°. Solid m-chloroperbenzoic acid (80%; 1.38 mmoles) was added portionwise over 5 minutes. The solution was stirred at 10° for a further 30 minutes and then concentrated to approximately 25 ml. Silica gel (approximately 10 g) was added and the remaining solvent removed. Flash chromatography using dichloromethane containing 20 % ethyl acetate as eluant gave a pale orange solid (0.20 g) which was slurried in dichloromethane (50 ml) and filtered to give the title compound as an off-white solid, mp 208°-9° (dec).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH:8]1[C:21]2[CH:20](O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(O)(C(F)(F)F)=O>[CH:8]1[C:21]2[CH:20]([S:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CSC1c2ccccc2Oc2ccccc21)C(=O)O
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A sample of 0.61 g of cysteine (5 mmole) was suspended in 100 ml of 1,2-dimethoxyethane and 2 ml of TFA. The suspension was stirred under nitrogen gas at room temperature until the solution became clear. To this clear solution was added 1 g of 9H-xanthen-9-ol (5.1 mmole) in one portion. The reaction mixture was stirred at room temperature for 30 minutes and was then neutralized to pH 7 by the addition of a saturated aqueous Na2CO3 solution. The mixture was then concentrated by rotary evaporation. The residue was diluted with 50 ml of water. The aqueous solution was treated with 10% aqueous citric acid solution to adjust the pH to 6. The mixture was stirred at room temperature for 1 hr. The resultant white solid was collected by filtration and was washed with 3×10 ml of water and 3×10 ml of ethyl acetate. The product was dried to yield 1.30 g of product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18](=[O:28])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH2:10]([O:17][C:18]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:27][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:24][CH:25]=1)=[O:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(CO)cc1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
Diisopropylethylamine (0.19 ml, 1.17 mmol) was added to a cool (0° C.) solution of (4-Hydroxymethyl-phenyl)-carbamic acid benzyl ester (0.25 g, 0.97 mmol) in DCM (8 ml) and the reaction stirred at this temperature for 5 minutes. After this time, methane sulfonyl chloride (0.09 ml, 1.07 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was then diluted with DCM (20 ml) and washed sequentially with saturated sodium bicarbonate solution (10 ml), saturated ammonium chloride (10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (0.29 g, 89% yield) as a yellow oil which was taken forward without further purification.
Reaction SMILES: CS(O[C@@H:6]1[CH2:9][CH2:8][C@@H:7]1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])(=O)=O.[NH2:21][CH2:22][CH2:23][OH:24]>C(OCC)(=O)C>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C@@H:7]1[CH2:8][CH2:9][C@H:6]1[NH:21][CH2:22][CH2:23][OH:24]
Reactant: CS(=O)(=O)O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Reactant: NCCO
Solvent: CCOC(C)=O
Product: OCCN[C@@H]1CC[C@H]1Oc1ccccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture of C8 (500 mg, 1.61 mmol) and 2-aminoethanol (5 mL) was heated at 90° C. for 18 hours, then at 100° C. for an additional 24 hours. The reaction was cooled, diluted with ethyl acetate (100 mL) and washed with aqueous sodium hydroxide solution (1 M, 5×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via HPLC (Column: Phenomenex Luna C18(2), 5 μm; Mobile phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in methanol; Gradient: 5% to 100% B) afforded the title compound as a solid. Yield; 191 mg, 0.694 mmol, 43%. LCMS m/z 276.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.49 (br s, 1H), 7.56 (br d, J=7.6 Hz, 1H), 7.44-7.50 (m, 1H), 7.04 (br dd, J=7.6, 7.6 Hz, 1H), 6.92 (br d, J=8.4 Hz, 1H), 4.90-4.97 (m, 1H), 3.75-3.90 (m, 3H), 2.99-3.15 (m, 2H), 2.46-2.56 (m, 1H), 2.21-2.31 (m, 1H), 1.90-2.02 (m, 1H), 1.77-1.89 (m, 1H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]([N:8]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9]1)([CH3:7])[CH3:6]>CC(C)=O.C(N(CC)CC)C>[CH:5]([N:8]1[CH:12]=[C:11]([O:13][C:3](=[O:4])[NH:2][CH3:1])[CH:10]=[N:9]1)([CH3:7])[CH3:6]
Reactant: CN=C=O
Reactant: CC(C)n1cc(O)cn1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)Oc1cnn(C(C)C)c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
6 g (0.105 mol) of methyl isocyanate were added to a solution of 12.6 g (0.1 mol) of 1-isopropyl-4-hydroxy-pyrazole in 100 ml of acetone and 2 drops of triethylamine. The mixture was stirred at 45° C. for 12 hours and the solvent was then distilled off in vacuo. 17.4 g (95% of theory) of N-methyl-carbamic acid O-(1-iso-propylpyrazol-4-yl) ester were thus obtained in the form of beige crystals with a melting point of 40° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]1.[N+:31](/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:33])=[O:32]>C1COCC1>[N+:31]([CH2:34][CH:35]([C:16]1([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18][CH2:19][N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][CH2:15]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C[N+](=O)[O-])c2ccccc2)CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of diisopropylamine (667 ul, 4.68 mmol) in THF (dry) (4 ml) was treated with n-BuLi (1.6M in hexanes) (2.93 ml, 4.68 mmol). After 5 minutes, the mixture was allowed to warm to RT and then re-cooled to −78° C. This mixture was added dropwise to a cooled (−78° C.) solution of 1-tert-butyl 4-methyl azepane-1,4-dicarboxylate (step 1) (927 mg, 3.6 mmol) in THF (4 ml). The reaction mixture was stirred at −78° C. for 40 minutes. To this mixture was added (E)-(2-nitrovinyl)benzene (537 mg; 3.6 mmol) in THF (4 ml) and the resulting mixture was allowed to warm slowly to RT. The reaction was quenched with saturated ammonium chloride solution and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane/EtOAc followed by 10-100% TBME in iso-hexane afforded the title compound as a diastereomeric mixture.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH2:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH2:30][CH3:31]>N.CO>[CH2:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH2:30][CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.1 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Propylbenzenesulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (12.8 mg). MS m/z 371 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][O:5]1)#[N:2].C(O)C>[Pd].C(O)(=O)C>[NH2:2][CH2:1][CH2:3][CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][O:5]1
Reactant: N#CCC1C=CC=CO1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: NCCC1C=CC=CO1

Procedure:
A mixture of rac 2-cyanomethylpyran (4.2 g) and 10% Pd/C (4.0 g) in 1:1 ethanol:acetic acid (150 ml) was hydrogenated at 55 psi overnight. The reaction mixture was filtered through Celite and the solvents were then removed in vacuo. The residue was partitioned between chloroform and 10% sodium carbonate solution. The organic phase was dried over sodium sulfate. Removal of the solvent gave the title compound:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])[CH3:32].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:31]([C:34]1[CH:39]=[CH:38][C:37]([O:1][C:2]2[CH:3]=[C:4]([C:14]3[N:15]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:16]([C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:17][CH:18]=3)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=2)=[CH:36][CH:35]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (92 mg, 0.214 mmol) synthesized in Example (38d) was dissolved in dichloromethane (10 mL), and 4-acetylphenylboronic acid (70 mg, 0.427 mmol), copper (II) acetate (60 mg, 0.330 mmol), triethylamine (0.15 mL, 1.08 mmol) and molecular sieves 4A (90 mg) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. The deposit of this reaction solution was Celite filtered. This mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-25%) to afford the desired compound (73 mg, yield 62%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[O:23][N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[CH2:1]([C:4]1[N:5]([CH2:20][C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)[O:23][N:22]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
A mixture of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.20 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.062 g, 0.24 mmol), Cs2CO3 (0.078 g, 0.24 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). Drying (MgSO4), filtration, and concentration were followed by purification (SiO2; 0-30% EtOAc in hexanes) to afford the title compound (0.070 g, 74%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.8 Hz, 1H), 8.24 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 5.88 (s, 2H), 2.89 (t, J=7.6 Hz, 2H), 1.78-1.61 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS m/z 479 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]#[N:25])[CH:23]=1>O>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:23]=3)[C:24]#[N:25])=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1cncc(Br)c1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cncc(C#N)c3)cc21

Procedure:
Prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 3-bromo-5-cyanopyridine according to Procedure B. Off-white solid: mp 290-291° C.; 1H-NMR (DMSO-d6) δ10.41 (s, 1H, D2O exchangeable), 9.21 (d, 1H, J=2.2 Hz), 8.97 (d, 1H, J=1.7 Hz), 8.68 (t, 1H, J=2.1 Hz), 7.76 (m, 2H), 7.01 (d, 1H, J=8.2 Hz), 1.70 (s, 6H); MS (ESI) m/z 278(M−H, 96%). Anal. Calc. For C16H13N3O2.0.2 H2O: C, 67.94, H, 4.77, N, 14.85. Found: C, 68.04, H, 4.70, N, 14.58.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](O)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1Cl
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1nccnc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.8 %

Procedure:
To a solution of 3-chloropyrazine-2-carboxylic acid (2.0 g, 12.70 mmol, 1.0 eq.) and TEA (3.50 mL, 25.40 mmol, 2.0 eq.) in THF (50 mL) was added methyl chloroformate (1.2 mL, 15.20 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (0.97 g, 25.40 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, quenched with NH4Cl(aq) solution, and extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-chloropyrazin-2-yl)methanol (400 mg, 22%) as a white solid. 1H NMR (400 MHz, MeOD) δ 8.58 (d, J=2.5 Hz, 1H), 8.38 (d, J=2.5 Hz, 1H), 4.84 (s, 2H). LRMS (M+H+) m/z 145.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:22])[CH2:18][CH:17]1[C:19](Cl)=[O:20]>O1CCCC1>[CH3:15][C:16]1([CH3:22])[CH2:18][CH:17]1[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CC1(C)CC1C(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: C1CCOC1
Product: CC1(C)CC1C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 69 %

Procedure:
5.0 g (26.4 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone, 4.2 g (31.7 millimoles) of 2,2-dimethylcyclopropanecarboxylic acid chloride in 100 ml of absolute tetrahydrofuran are refluxed for 7 hours. The mixture is concentrated to about 50 ml and the product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 5.2 g (68% of theory) of 4,5-dihydro-6-[p-(2,2-dimethylcyclopropylcarbonylamino)-phenyl]-3(2H)-pyridazinone quarter-hydrate are obtained as almost colorless crystals, of melting point 213°-214° C.