Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](=[C:14]2[S:19][CH2:18][S:17][CH2:16][S:15]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:6](=[C:14]2[S:15][CH2:16][S:17](=[O:30])[CH2:18][S:19]2)[C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(C(=C2SCSCS2)c2ccc(F)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S1CSC(=C(c2ccc(F)cc2)c2ccc(F)cc2)SC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a 30 ml of dichloromethane of 1.5 g of 2-(4,4'-difluorobenzhydrylidene)-1,3,5-trithiane was added 0.77 g of m-chloroperbenzoic acid in small portions at 0° C., and the resulting mixture was stirred overnight. After completion of the reaction, the reaction mixture was poured into ice-water and extracted with dichloromethane. Usual work up gave crude solid, which was purified by a silica gel column chromatography (chloroform:hexane=3:1) to obtain 1.2 g of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[N:3]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[N:10]([CH3:9])[C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: Clc1cccc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(-c2cccc(Cl)n2)cc2ccccc21
Yield: 100.2 %

Procedure:
2-Chloro-6-iodopyridine (400 mg, 1.67 mmol), N-methylindole-2-boronic acid (292 mg, 1.67 mmol), tetrakis(triphenylphosphine)palladium (0) (154 mg, 0.13 mmol) and Na2CO3 (442 mg, 4.18 mmol) were dissolved in water (10 mL) and dioxane (10 mL) and heated using a microwave (110° C., absorption high) for 1 h. The solvents were removed in vacuo and the residue was partitioned between DCM (50 mL) and water (30 mL). The aq fraction was extracted with DCM (30 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude title compound (406 mg) as a brown gum. LCMS (ES+): 243.2 [MH]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[NH:17][C:16](=[O:18])[C:15]([C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:14][N:13]=2)C[CH2:2]1.[O:24]=[C:25]1NC(C2C=C(OC)C=CC=2OCCC)=NC=C1C#N>>[CH3:25][O:24][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:1][CH3:2])=[C:7]([C:12]2[NH:17][C:16](=[O:18])[C:15]([C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:14][N:13]=2)[CH:8]=1
Reactant: CCCOc1ccc(OC)cc1-c1ncc(C#N)c(=O)[nH]1
Reactant: O=c1[nH]c(-c2ccccc2OCC2CC2)ncc1-c1nnn[nH]1
Product: CCCOc1ccc(OC)cc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1

Procedure:
In a manner similar to that described for the preparation of 2-(2-cyclopropylmethoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one in Example 9, the title compound was prepared from 1,6-dihydro-6-oxo-2-(5-methoxy-2-n-propoxyphenyl)pyrimidine-5-carbonitrile. The crude product was recrystallized from 2-methoxyethanol to give analytical material (65%), m.p. 257°-260°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])[CH:6]=[C:7]1[S:11][C:10](SC)=[N:9][C:8]1=[O:14].[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:28])[F:27])[CH:6]=[C:7]1[S:11][C:10]([N:29]2[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]2)=[N:9][C:8]1=[O:14]
Reactant: O=C(O)C1CNC1
Reactant: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccccc1C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C=C2SC(N3CC(C(=O)O)C3)=NC2=O)ccc1Oc1ccccc1C(F)(F)F

Procedure:
was prepared from 5-[3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid and substituting MeCN with DMF as described in Example 5C
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]([C:20]1[C:21]([CH3:30])=[C:22]([C:27]([OH:29])=[O:28])[NH:23][C:24]=1[CH:25]=O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([C:20]1[C:21]([CH3:30])=[C:22]([C:27]([OH:29])=[O:28])[NH:23][C:24]=1[CH:25]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][C:6]1=[O:11])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(C(=O)O)[nH]c(C=O)c1C(=O)c1ccccc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C(=O)c1ccccc1

Procedure:
5-Bromo-1,3-dihydro-indol-2-one was condensed with 4-benzoyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid using method D to give 4-benzoyl-5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH:30]([C:32]1[O:33][C:34]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=1)[OH:31])(C(C)(C)C)(C)C>>[CH3:42][O:41][C:40]1[C:34]2[O:33][C:32]([CH:30]([OH:31])[CH2:29][CH2:28][CH2:27][OH:26])=[CH:36][C:35]=2[CH:37]=[CH:38][CH:39]=1
Reactant: COc1cccc2cc(C(O)CCCO[Si](C)(C)C(C)(C)C)oc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cccc2cc(C(O)CCCO)oc12
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Tetrabutylammonium fluoride (12 ml, 1M in tetrahydrofuran) was added to a stirred solution of 4-(tert-butyldimethylsilanyloxy)-1-(7-methoxybenzofuran-2-yl)-butan-1-ol (4 g) in tetrahdrofuran (50 ml) at 0° C. After stirring cooled for 2 hours the reaction was warmed to room temperature and allowed to stir for a further 1 hour. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (50 ml). The organic extract was dried over magnesium sulphate, filtered and preadsorbed onto silica. Purification by column chromatography on silica eluting with ethyl acetate yielded the title compound as a tan oil (2.34 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([C:8]([Cl:13])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(Cl)sc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)sc1C(=O)Cl

Procedure:
8.8 g of 2-chloro-4-methylthiazole-5-carboxylic acid was suspended in 7 ml of thionyl chloride, and one drop of N,N-dimethylformamide was added. The mixture was heated under reflux for 1 hour, and then the excess of thionyl chloride was evaporated under reduced pressure. Benzene (10 ml) was added, and the mixture was evaporated under reduced pressure. This procedure was repeated three times to give 9.7 g of 2-chloro-4-methylthiazole-5-carboxylic acid chloride which was used in the following reaction without purification.
Reaction SMILES: [CH2:1]1[C@H:9]([OH:10])[C@H:8]2[N:3]([CH2:4][C@H:5]([OH:13])[C@@H:6]([OH:12])[C@@H:7]2[OH:11])[CH2:2]1.[C:14](OC=C)(=[O:16])[CH3:15]>>[C:14]([O:10][CH:9]1[CH:8]2[N:3]([CH2:4][CH:5]([OH:13])[CH:6]([OH:12])[CH:7]2[OH:11])[CH2:2][CH2:1]1)(=[O:16])[CH3:15]
Reactant: O[C@H]1[C@H](O)[C@@H](O)CN2CC[C@H](O)[C@H]12
Reactant: C=COC(C)=O
Product: CC(=O)OC1CCN2CC(O)C(O)C(O)C12
Yield: 91 %

Procedure:
The same general procedure was repeated using castanospermine and vinyl acetate (2.2 mmol) and a reaction time of 84 hours to give [1S-(1α, 6β,7α, 8β, 8aβ)]-octahydro-1,6,7,8-indolizinetetrol 1-acetate melting at about 151°-153° C. (yield, 91%)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[N:4][CH:3]=1.[SH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([S:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Br)s1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 111.2 %

Procedure:
A solution of the product of Example 202A (300 mg, 0.8274 mmol) in anhydrous N,N-dimethylformamide (8 mL) was treated with 4-mercaptophenol (104.4 mg, 0.8274 mmol) and cesium carbonate (539 mg, 1.655 mmol) at room temperature, then heated at 100° C. under a nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The residue was taken up in water (50 mL) and the pH adjusted to 3 with 1N aqueous HCl. The aqueous was extracted with ethyl acetate (100 mL), and the organic extract washed with water (2×25 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give the product as a golden-brown solid (416 mg, 111%).
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][C:14]=3[F:25])[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12.C(O)(=O)C.Cl>O>[F:34][CH:2]([F:1])[O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[F:25])[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OC(F)F)C2=O)c(F)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOc1c2c(c(OC(F)F)c3ccccc13)CN(c1ccc(CC(=O)O)cc1F)C2=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Ethyl {-4-[4-[(difluoromethyl)oxy]-9-(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.60 g, 1.27 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:2N aqueous hydrochloric acid (20 ml) for 50 minutes. The reaction was cooled to room temperature. On addition of water, the resulting white solid was collected by filtration, washed with water and dried under vacuum to give the title compound (0.516 g, 1.09 mmol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](F)[C:3]=1[C:4]([OH:6])=[O:5].Cl.CN.[CH2:16]([N:18](CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:18][CH3:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1c(F)cc(F)cc1F
Agent: CN
Agent: Cl
Solvent: c1ccncc1
Product: CNc1cc(F)cc(F)c1C(=O)O
Temperature: 110 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
To a solution of 2,4,6-trifluorobenzoic acid (6.0 g, 34.1 mmol) and methylamine hydrochloride (12.0 g, 170 mmol) in pyridine (24 mL), triethylamine (24 mL, 170 mmol) was added. The reaction was stirred at 110° C. for 15 h and then concentrated in vacuo. The residue was acidified with 1N HCl (100 mL). The precipitate was collected by filtration to give 5.83 g of clean desired product as an orange solid (91%). 1H NMR (400 MHz, DMS O-d6): δ 13.09 (s, 1H), 7.91 (s, 1H), 6.33 (s, 1H), 6.30 (s, 1H), 2.81 (s, 3H). MS (ES) [m+H] calc'd for C8H7F2NO2, 188; found 188.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[CH:13]=[C:14]([C:22]2[O:26][CH:25]=[N:24][C:23]=2[CH3:27])[CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19].[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:25]1[O:26][C:22]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([F:19])([F:21])[F:20])=[C:12]([Cl:11])[CH:13]=2)=[C:23]([CH3:27])[N:24]=1
Reactant: Cc1ncoc1-c1ccc(C(F)(F)F)c(Cl)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.9 %

Procedure:
LiHMDS (1.0 M in THF, 13 ml, 13 mmol) was added slowly via syringe to a solution of Example 45B (3.04 g, 11.6 mmol) in THF (50 mL) at −78° C. The solution was stirred 45 min, and then solid hexachloroethane (4.13 g, 17.4 mmol) was added in one portion. The reaction was allowed to proceed for 12 hr with gradual warming to ambient temperature. The reaction was quenched with half-saturated aq NH4Cl solution, and the product was extracted with Et2O. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (Analogix® Intelliflash 280™; 0% to 20% EtOAc/hexanes eluant; SF40-150 g column) to afford 3.02 g (88%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=8.4, 1H), 7.86 (s, 1H), 7.75 (d, J=8.3, 1H), 2.42 (s, 3H). MS (DCI+) m/z 296 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.[OH-].[Na+]>C(O)C.Cl>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[OH:1])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(C)cc2O)OCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(C)cc2O)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 18.5 %

Procedure:
To a solution of ethyl 2-[(2-hydroxy-4-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.061 g, 0.42 mmol) in ethanol (2.5 mL), 2M hydrochloric acid in ethanol (0.56 mL, 1.1 mmol) was added at ambient temperature. The mixture was refluxed for 19 h. Cooled with ice bath, 2M sodium hydroxide solution (0.49 mL, 0.97 mmol) was added dropwise to neutralize, and ethanol (8.0 mL) was added and the mixture was refluxed for 30 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.027 g, y. 18%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:31])[C:12]=1[C:13](=[O:30])[NH:14][C:15]1[N:20]=[CH:19][N:18]2[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=[C:17]2[CH:16]=1)=[O:7])C.Cl>C(O)C>[CH3:31][N:11]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[N:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[CH:16]=2)=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C

Procedure:
KOH (15 ml of a solution of 0.26 g in 25 ml ethanol) was added to 1-Methyl-5-(2-phenyl-imidazo[1,2-c]pyrimidin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 83), and the mixture was heated to reflux overnight. The mixture was cooled to r.t. and acidified with HCl (25%, 0.7 ml). The precipitate was filtered, washed with a small amount of ethanol, and dried under vacuum. The obtained title compound was used without further purification in the next step. MS (m/e)=363.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH:14]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][NH:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCCC1CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1CCNC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 38 (2.3 g, 10.80 mmol) in DCM (90 mL) were added successively 2-aminoindane (1.4 mL, 10.80 mmol), Na(OAC)3BH (6.86 g, 32.39 mmol) and acetic acid (2 mL) at 0° C. The resulting mixture was allowed to stir at rt for 16 hours. The reaction mixture was diluted in DCM and washed with 1N NaOH, water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM to provide compound 39.
Reaction SMILES: Cl.[C:2]1([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>O1CCOCC1>[C:2]1([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH3:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(c1ccccc1)N1CCC[C@H](C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(c1ccccc1)N1CCC[C@H](C(=O)O)C1
Reaction time: 0.5 h

Procedure:
In a flask, hydrochloric acid in dioxane (4M, 2 mL) was added to (3S)-tert-butyl 1-(1-phenylethyl)piperidine-3-carboxylate (0.031 g, 0.108 mmol), and the reaction was stirred for 30 minutes. Ethanol (2 mL) was added to the reaction, and the resulting solution was concentrated in vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[N:11][C:12]([O:15]C)=[CH:13][CH:14]=1.[OH-].[NH4+]>I.O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[N:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2c(C)cccc2C)nn1
Agent: I
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(C)c1-c1ccc(O)nn1
Temperature: 80 °C

Procedure:
A mixture of 3-(2,6-dimethyl-phenyl)-6-methoxy-pyridazine (1.6 g, 7.47 mmol) in hydriodic acid (57% in water, 10 mL) is heated at 80° C. for 2.5 h. The cooled mixture is diluted with water, neutralized to pH 7 with ammonium hydroxide and extracted with EtOAc. The extract is washed with water, dried and concentrated to yield 6-(2,6-dimethyl-phenyl)-pyridazin-3-ol as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: O=C1NCC[C@@H](c2ccc(O)cc2)[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc([C@@H]2CCNC(=O)[C@H]2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2.67 g (0.01 mol) of trans-4-(4-hydroxyphenyl)-3-phenyl-2-piperidone 27 dissolved in 20 cm3 of anhydrous pyridine, 2 cm3 (0.028 mol) of acetyl chloride are added under nitrogen at 0° C. The mixture is stirred for 2 hours 30 mins at 0° C., and then 48 hours at room temperature. The reaction mixture is then poured onto 50 g of ice. A spatulaful of sodium bicarbonate is added, and the mixture is stirred and then extracted with methylene chloride (3 times 60 cm3).
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:8])[O:6][CH3:7])#[N:3].[N:9]#[C:10]N>C1C=CC=CC=1>[C:10]([N:8]=[C:5]([O:6][CH3:7])[CH2:4][C:2]#[N:3])#[N:9]
Reactant: N#CN
Reactant: COC(=N)CC#N
Agent: Cl
Solvent: c1ccccc1
Product: COC(CC#N)=NC#N
Yield: 91.8 %

Procedure:
2.69 g of methyl cyanoacetimidate hydrochloride, 1.68 g of cyanamide and 5.0 g of molecular sieve (type 4A, 60 mesh through) were suspended in 30 ml of benzene and the suspension was made to react for 5 hours at 25°C under stirring. After reaction, insoluble materials were filtered off and then the filtrate was concentrated to dryness in vacuo to give 2.26 g of methyl N-cyanocyanoacetimidate (yield 91.2%) mp 45.5°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22].[F:26][C:27]([F:40])([F:39])[C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32](O)=[O:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][N:12]([C:32](=[O:33])/[CH:31]=[CH:30]/[C:29]3[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=3[C:27]([F:39])([F:40])[F:26])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23]
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Reactant: C[Si](C)(C)CCOC(=O)NC1CC2(CCNCC2)c2c(Br)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a stirred solution of (±)-2-(trimethylsilyl)ethyl 7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (23 mg, 0.056 mmol), ortho-(trifluoromethyl)cinnamic acid (16 mg, 0.074 mmol) and i-Pr2NEt (0.027 mL, 0.15 mmol) in CH2Cl2 (3 mL) was added solid HATU (28 mg, 0.0.074 mmol). The mixture was stirred overnight at rt and evaporated to leave a residue which was purified by preparative HPLC to afford (±)-(E)-2-(trimethylsilyl)ethyl 7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (16.5 mg, 47%). LC-MS Method 1 tR=2.37 min, m/z=623, 625.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3C(OC(C)(C)C)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][NH:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc([N+](=O)[O-])nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2C[C@@H]3C[C@H]2CN3)cn1

Procedure:
The product from Example 3A was treated with trifluoroacetic acid:methylene chloride (1:2) at ambient temperature for 2 hours. The volatiles were removed under reduced pressure, and the residue was purified on SiO2 (5% MeOH/CH2Cl2/1%NH4OH) to provide the title compound as a yellow gum. MS (DCI/NH3) m/z 221 (M+H)+, 238 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:3]=1.[H-].[Na+].[H][H]>CC(O)C>[CH:22]([O:24][C:2]1[CH:3]=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:7]=1)([CH3:23])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(N)cc2)n1
Temperature: 140 °C

Procedure:
In a 2-5 mL microwave vial was placed 3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13, 70 mg, 0.202 mmol) in 2-propanol (4 mL) to give a yellow suspension. Sodium hydride (60% in oil, 32.3 mg, 0.807 mmol) was added and the mixture was stirred until no further formation of hydrogen gas was observed. The reaction was heated under microwave irradiation at 140° C. for 30 min to give a bright orange suspension. Work-up: the solvents were evaporated. The residue was dissolved in dichloromethane and washed with sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to give the title compound in a quantitative yield.