Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[C:11]1[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:11]2[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: COc1ccc(S)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cc(C(=O)O)co2)cc1
Yield: 42.5 %

Procedure:
By the procedure of Example 11, p-methoxythiophenol (4.39 g., 31.4 mmoles) and cuprous oxide (2.25 g., 15.7 mmoles) heated at 135° C. for 2 hours were reacted with 5-bromofuran-3-carboxylic acid (3 g., 15.7 mmoles) in 60 ml. of dimethylformamide, and crude product (1.67 g. ) isolated. Recrystallization from methylene chloride/hexane gave purified 5-(4-methoxphenylthio)furan-3-carboxylic acid (825 mg., m.p. 115°-117° C., m/e 250).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CCN1CCC(CN)C1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CCN1CCC(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and (1-ethylpyrrolidin-3-yl)methanamine (12.8 mg, 0.1 mmol). The title compound was obtained as a solid (10.7 mg, 23% yield). MS ink: 460.87, 462.87 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7]([OH:9])=O.[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:7]([C:6]3[S:5][C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:3][C:2]=3[CH3:1])=[O:9])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)O
Product: Cc1nc(-c2ccccc2)sc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 1 above, 4-methyl-2-phenyl-thiazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 4-methyl-2-phenyl-thiazole-5-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C20H20N4O2S (m/e) 380, obsd 381 (M+H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21]C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](OC)=O>>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][NH2:21])[CH2:18][CH2:19]1)[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC=O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Product: CN(CCCCCN1CCC(CN)CC1)Cc1ccccc1

Procedure:
A solution of N-benzyl-5-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (3.7 g) in methyl formate (30 ml) was refluxed under heating for 12 hr. After cooling, methyl formate was evaporated, and tetrahydrofuran (40 ml) and 2M trifluoroborane-dimethyl sulfide solution (19 ml) were added to the residue, which was followed by refluxing under heating for 6 hr. The solvent was evaporated, and ethanol (40 ml) and hydrochloric acid (3 ml) were added to the reaction mixture, which was followed by refluxing under heating for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3.60 g of N-benzyl-N-methyl-5-(4-aminomethylpiperidin-1-yl)pentylamine.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH:5]([O:35][CH2:36][CH3:37])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH2:15][CH2:16][CH3:17])=[CH:9][C:8]=1[CH3:34])C.[Li+].[OH-]>>[CH2:36]([O:35][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:18]2[S:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)=[N:20][C:19]=2[CH3:33])[CH2:15][CH2:16][CH3:17])=[CH:9][C:8]=1[CH3:34])[C:4]([OH:38])=[O:3])[CH3:37]
Reactant: CCCC(Oc1ccc(CC(OCC)C(=O)OCC)c(C)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Li+]
Agent: [OH-]
Product: CCCC(Oc1ccc(CC(OCC)C(=O)O)c(C)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C

Procedure:
In analogy to the procedure described in example 10 d], 2-ethoxy-3-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butoxy}-phenyl)-propionic acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 2-ethoxy-3-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butoxy}-phenyl)-propionic acid as a mixture of two diastereomeric racemates as colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([CH:23]([CH3:25])[CH3:24])=[C:12]([CH2:21][OH:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][C:11]([CH:23]([CH3:25])[CH3:24])=[C:12]([CH:21]=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1nnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
1.8 g (5.5 mmol) of the compound from Example 7a in 30 ml of dichloromethane are poured into a suspension of 1.8 g (0.4 mmol) of PCC in 30 ml of dichloromethane at room temperature. After stirring at room temperature for 3 h, 3 volumes of ether are added, and the mixture is filtered through silica gel. Removal of the solvent in vacuo, and chromatography on silica gel (cyclohexane/ethyl acetate 1) yields 1.5 g of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27]C(=O)OC(C)(C)C)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[ClH:35]>O1CCOCC1.CCOCC>[ClH:35].[NH2:27][C@H:22]1[C:23]2[C:19](=[C:18]([C:15]3[O:14][C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([CH:4]=4)[C:1]#[N:2])=[N:17][CH:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)o2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4N)o2)cc1C#N
Temperature: 60 °C
Yield: 78 %

Procedure:
To a stirring solution of (R)-tert-butyl 4-(2-(3-cyano-4-isopropoxyphenyl)oxazol-5-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-42 (48 mg, 0.1 mmol) in 1,4-dioxane (1 mL) was added a 4N HCl solution in 1,4-dioxane (1 mL). The reaction mixture was heated at 55-65° C. for 48 h. The cooled reaction mixture was diluted with Et2O (10 mL). The resulting solid was collected and dried under high vacuum to yield 32 mg (78%) of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 59 as a white solid. LCMS-ESI (m/z) calculated for C22H21N3O2: 359.4; found 343.1 [M−NH2]+, tR=2.40 min. 1H NMR (400 MHz, DMSO) δ 8.55 (br s, 2H), 8.43 (dd, J=6.5, 2.4 Hz, 1H), 8.32 (ddd, J=6.7, 6.1, 2.9 Hz, 1H), 8.00 (t, J=13.5 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.49 (dd, J=8.5, 6.3 Hz, 2H), 4.93 (dt, J=12.1, 6.0 Hz, 1H), 4.81 (s, 1H), 3.43-3.25 (m, 1H), 3.23-3.04 (m, 1H), 2.67-2.55 (m, 1H), 2.11 (ddd, J=14.2, 9.0, 5.9 Hz, 1H), 1.36 (dd, J=13.8, 7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:15](=[N:14][C:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)([CH2:25][CH:24]=[CH2:23])[C:4]([O:3][CH2:1][CH3:2])=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCBr
Reactant: CCOC(=O)C(N=Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: C=CCC(N=Cc1ccccc1)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Ethyl(benzylidene-amino)-(3,4-dichlorophenyl)-acetate (1.41 mol) was dissolved in ethyl acetate (2.3 L). Allyl bromide (341 g), potassium carbonate (390 g), and tetrabutylammonium bromide (45 g) were added to the resultant mixture, followed by refluxing for 2.5 hours. The reaction mixture was left to cool to room temperature. The mixture was sequentially washed with water and saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (500 g, 94%).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]2[CH2:12][C:7]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)([CH2:8]2)[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C>C(O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]23[CH2:8][CH:9]([CH2:12]2)[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]3=[O:22])=[CH:18][CH:17]=1
Reactant: CCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 2.08 g of 3-n-butyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 60 ml of ethanol are hydrogenated in the presence of 0.15 g of palladium-on-carbon and worked up. Melting point 178°-179° (from ethyl acetate).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]3[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[C:26]([CH:33]([CH3:35])[CH3:34])[C:25]=3[O:36][CH2:37][CH3:38])=[CH:22][N:23]=2)[CH:20]=1)=O>ClCCl>[CH2:37]([O:36][C:25]1[C:26]([CH:33]([CH3:34])[CH3:35])=[CH:27][C:28]([CH:30]([CH3:32])[CH3:31])=[CH:29][C:24]=1[C:21]1[N:19]2[CH:20]=[C:15]([CH2:13][OH:12])[CH:16]=[CH:17][C:18]2=[N:23][CH:22]=1)[CH3:38]
Reactant: CCOc1c(-c2cnc3ccc(C(=O)OC)cn23)cc(C(C)C)cc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCOc1c(-c2cnc3ccc(CO)cn23)cc(C(C)C)cc1C(C)C
Temperature: -78 °C
Reaction time: 4 h
Yield: 36.6 %

Procedure:
Diisobutylaluminum hydride (2.4 ml, 1M soln., 2.4 mmol) was added dropwise to a solution of 3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (300 mg, 0.79 mmol) in dichloromethane (10 mL) which had been cooled to −78° C. under a nitrogen atmosphere. After the addition was complete, the reaction was kept at −78° C. for 4 h, then quenched with with methanol (10 mL). After addition of the methanol, the mixture was poured into water, filtered and the solution evaporated to a residue. The residue was purified by silica gel chromatography (2.5% MeOH in dichloromethane) to give [3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-methanol as a clear glass (102 mg, 38%). 1H NMR (250 MHz, CDCl3): δ 8.01 (s, 1H), 7.70 (bs, 1H), 7.64 (d, 1H, J=9.4), 7.24 (m, 2H), 7.12 (d, 1H, J=0.62), 4.73 (s, 1H), 3.45 (m, 1H), 3.35 (q, 2H, J=7.0), 1.34 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H), 0.84 (t, 3H, J=7.0), MS [EI+] 353 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(#N)C.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1)[CH3:13]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(N)=O)cc1
Temperature: 80 °C

Procedure:
Potassium carbonate (1.04 g) and ethyl bromoacetate (0.610 ml) were added to an acetonitrile (15 ml) solution containing 4-hydroxybenzamide (686 mg), followed by heating at 80° C. for 2 hours. The reaction solution was cooled, water (45 ml) was added thereto, and the precipitated solid was collected by filtration, washed with water and dried to obtain ethyl[4-(aminocarbonyl)phenoxy]acetate (893 mg) as pale brown powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:38][O:39][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]3=[O:37])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=4[O:39][CH2:38]3)[C:16]2=[O:37])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A suspension of 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.00 g, 2.0 mmol) in methanol/ethyl acetate (15/25 mL) was degassed by bubbling through nitrogen for 1 h before palladium on carbon (5%, 0.42 g, 0.2 mmol) was added. The mixture was stirred under hydrogen at ambient temperature for 16 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The obtained residue was recrystallized from ethyl acetate and hexane to afford 1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.78 g, 95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.42-7.25 (m, 10H), 7.16-7.10 (m, 1H), 7.07-6.92 (m, 3H), 6.54-6.48 (m, 1H), 6.44 (d, J=8.2 Hz, 1H), 6.33 (d, J=2.2 Hz, 1H), 6.20 (dd, J=8.2, 2.2 Hz, 1H), 5.65 (s, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H); MS (ES+) m/z 420.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][C:7](=[O:17])[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[NH2:20][C:4]1[CH:3]=[CH:2][C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][C:7](=[O:17])[C:6]=2[C:5]=1[O:18][CH3:19]
Reactant: [H][H]
Reactant: COc1c([N+](=O)[O-])cc(Cl)c2c1C(=O)C[C@@H](NC(C)=O)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1c(N)ccc2c1C(=O)C[C@@H](NC(C)=O)CC2
Yield: 133.4 %

Procedure:
632 g) N—((S)-4-Chloro-1-methoxy-2-nitro-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide (100 mg, 0.3 mmol), 20% Pd(OH)2/C (30 mg) and Methanol (20 mL) were placed under a blanket of Hydrogen at atmospheric pressure. After 24 h the reaction mixture was filtered and the filtrate concentrated under reduced pressure to yield 105 mg (100%) of N—((S)-2-Amino-1-methoxy-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide; hydrochloride. TLC: 5:1 CH2Cl2:MeOH Rf 0.5 homogeneous; (SM A: Rf 0.55); 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J=8.09 Hz, 1H), 7.01 (m, 1H), 6.86 (d, J=8.09 Hz, 1H), 3.95 (m, 1H), 3.66 (s, 3H), 3.5 (bs, water+NH2), 2.79-2.64 (m, 4H), 1.95-1.85 (m, 1H), 1.78 (s, 3H), 1.7-1.6 (m, 1H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].C1C=CC=CC=1.[OH-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27]>O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26]([N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8])=[O:27]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1c(Cl)cccc1Cl

Procedure:
To a slurry of 6.73 g (0.05 mole) of 2-imino-1-methylpyrrolidine hydrochloride in 75 ml. of dry benzene is added, with stirring, 2 ml. of water, followed by 6 ml. of 50% NaOH. The benzene is decanted onto anhydrous K2CO3 and the aqueous layer washed twice with 50 ml. portions of benzene, the benzene being collected by decanting onto the K2CO3. The benzene extracts are put under nitrogen and dried for 15 minutes, then filtered rapidly through diatomaceous earth (nitrogen blanket) and washed with 100 ml. of benzene. To the filtrate is added 9.4 g. (0.05 mole) of 2,6-dichlorophenylisocyanate, put under nitrogen, stoppered and stirred at room temperature for 2 hours. The mixture is filtered and the solvent removed under reduced pressure. Trituration of the oily residue results in crystallization, 1-(2,6-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea, and the white crystals are filtered and collected. After recrystallization from benzene-ether-petroleum ether, the m.p. is 134°-136° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([NH:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)[N:7]=[C:6]([CH:26]([F:28])[F:27])[C:5]=2[C:4](=[O:29])[CH2:3]1.C([OH:33])C.CS(C)=O.[OH-].[Na+].OO>O>[CH3:1][C:2]1([CH3:30])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:33])=[C:13]([NH:19][CH:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:12]=3)[N:7]=[C:6]([CH:26]([F:27])[F:28])[C:5]=2[C:4](=[O:29])[CH2:3]1
Reactant: CCO
Reactant: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C#N)c(NC4CCOCC4)c3)c2C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C(N)=O)c(NC4CCOCC4)c3)c2C1
Yield: 93 %

Procedure:
To a solution/suspension of 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (897 mg, 2.16 mmol, 1.0 eq) in 10.8 mL of 4:1 mixture of ethanol-dimethyl sulfoxide was added 1 mL of 1 M aqueous sodium hydroxide and 1 mL of 30% hydrogen peroxide. After 30 minutes the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound, 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, (869 mg, 93%) as a tan solid: LC/MS (m/z): [M+H]+ 433.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](B(O)O)=[C:12]2[CH:11]=[N:10]1.Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO.COCCOC.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[N:26][CH:27]=3)=[C:12]2[CH:11]=[N:10]1
Reactant: Nc1ncncc1Br
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Nc1ncncc1-c1ccnc2c1cnn2-c1ccc(F)cc1F
Temperature: 110 °C
Yield: 34.2 %

Procedure:
Example 67 was prepared according to the general procedure in Example 1, except heating at 110° C. for 4.5 h, and using the following materials: Intermediate 63A (308 mg, 1.120 mmol), 5-bromopyrimidin-4-amine (297 mg, 1.707 mmol), sodium carbonate (484 mg, 4.57 mmol), EtOH:DME:H2O (1.2:2.5:1.0 ratio) (5.0 mL) and tetrakis(triphenylphosphine) palladium(0) (81 mg, 0.07 mmol). Example 67 was isolated as a white solid (124.2 mg, 32.3%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 15% Solvent B to 80% Solvent B over 12 min, ret. T=6.0 min. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.65 (1 H, d, J=4.88 Hz), 8.51 (1 H, s), 8.37 (1 H, s), 8.28 (1 H, s), 7.77 (1 H, td, J=8.70, 6.10 Hz), 7.60-7.70 (1 H, m), 7.31-7.45 (2 H, m), 6.98 (2 H, br. s.). LC/MS (Condition B): ret. T=1.99 min, (M+H)+ 325.04. Analytical HPLC: (Condition A): >99%, ret. T=15.36 min, (Condition B): >99%, ret. T=16.81 min, (Condition C): >99%, ret. T=5.47 min, (Condition D): >99%, ret. T=5.81 min.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CC(C)=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[C:20]([F:19])([F:29])[F:30])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3ccccc3C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
To a solution of 2-cyano-6-hydroxybenzothiazole (100 mg, 0.568 mmol) in 10 mL of acetone was added potassium carbonate (157 mg, 1.14 mmol), followed by 2-(trifluoromethyl)benzyl bromide (204 mg, 0.852 mmol). The mixture was then stirred at RT for about 5 hrs. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. The resultant solution was then extracted with dichloromethane. The organic phase was dried over sodium sulfate and purified by flash chromatography using dichloromethane. 148 mg of product was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1>[CH2:12]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]=[O:27])=[CH:3][CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(CCCOCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(CCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzyl 3-(4-bromophenyl)propyl ether (3.59 g, 11.77 mmol) in tetrahydrofuran (32 mL) at −75° C. under an argon atmosphere was added n-butyllithium (1.6 M in hexane, 8.83 mL). The solution was stirred for 15 min, and N,N-dimethylformamide (1.09 mL, 14.13 mmol) was added dropwise. The reaction was stirred for another 30 min and than warmed to room temperature, quenched with aqueous ammonium chloride solution, extracted with tert-butyl methyl ether and concentrated in vacuo. The crude product was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[CH:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[CH:32]=[CH:31][C:24]4[N:25]=[C:26]5[N:30]([C:23]=4[CH:22]=2)[CH2:29][CH2:28][S:27]5)(Br)[C:14]3=[O:37])=[O:11])=CC=1)([O-])=O.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[S:27]1[C:26]2=[N:25][C:24]3[CH:31]=[CH:32][C:21](/[CH:20]=[C:15]4\[C@@H:16]5[N:13]([C:14]\4=[O:37])[C:12]([C:10]([OH:11])=[O:9])=[CH:18][S:17]5)=[CH:22][C:23]=3[N:30]2[CH2:29][CH2:28]1
Reactant: [H][H]
Reactant: CC(=O)OC(c1ccc2nc3n(c2c1)CCS3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CSC21
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5n(c4c3)CCS5)C(=O)N12
Yield: 8.1 %

Procedure:
6-[Acetoxy-(2,3-dihydro-benzo[4,5]imidazo[2,1-b]thiazol-6-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (690 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 32 mg of product (Yield 3%) was collected. MP: >250° C.; H-NMR (D2O): □ 7.08 (m, 6H), 7.36 (s, 1H), 4.05 (m, 2H), 3.90 (b, 1H); MS: 358.3 (M+H).