Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3](I)[CH:2]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>>[CH3:19][Si:18]([C:16]#[C:17][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=2)=[CH:1][CH:2]=1)([CH3:21])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(Cc2ccc(I)cc2)cc1
Product: C[Si](C)(C)C#Cc1ccc(Cc2ccc(C#C[Si](C)(C)C)cc2)cc1

Procedure:
In Step II, 4,4'-diiododiphenylmethane [Compound (2)] was then coupled with ethynyltrimethylsilane [Compound (3)] to form an end-protected bis(4 trimethylsilylethynylphenyl) methane [Compound (4)] by forming a solution comprising 8.40 g (20.0 mmoles) of 4,4'-diiododiphenylmethane and 2.50 g (25.5 mmoles) of ethynyltrimethylsilane in 150 ml of 2:1 triethylamine toluene deaerated with argon. This solution was subsequently treated with a catalyst mixture comprising 50 mg of dichlorobis(triphenylphosphine)palladium[II], 150 mg of triphenylphosphine and 50 mg of copper[I] iodide. The yellow solution thus obtained was stirred and warmed to 80°-90° C. over 1 hour and kept in this temperature range for 4 hours. A copious white precipitate was formed which was filtered off after cooling to 25° C. and diluting with 150 ml of ether. The yield of triethylamine hydroiodide [Compound (5)] was quantitative. The filtrate was concentrated to a thick oil, dissolved in 200 ml of ether and washed with 200 ml each of 10% aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and water again. The ethereal phase was dried over magnesium sulfate and concentrated to an oil which crystallized on standing. The solid was taken up in 100 ml of 1:1 hexane/dichloromethane and filtered through a bed of silica gel. The filtrate was evaporated down to half of the original volume and cooled at -78° C. to precipitate 7.20 g (20.0 mmoles; 100%) of a crystalline solid. Recrystallization from hexane yielded pure, lustrous crystals in 81% recovery: mp 110°-111° C.; IR (KBr) 2970 (strong, sharp, SiCH3), 2160 (strong, sharp, C≡C), 1505 (strong, sharp, C=C), 1250 (strong, sharp, SiCH3) and 840 cm (very strong, broad, Si--C bending); NMR (CDCl3) δ0.28 (s, 18H, SiCH3), 3.92 (s, 2H, CH2), 7.37 and 7.40 ppm (q, 8H, JAB =8.0 Hz, aromatic).
Reaction SMILES: [CH:1]12[C:9](=[O:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]=[CH:3][CH2:2]2.[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:10]1[CH2:11][CH2:12][O:13][C:9]21[CH:6]1[CH2:7][CH2:8][CH:1]2[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: O=C1C2CC=CCC1CC2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=CCC2CCC(C1)C21OCCO1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of bicyclo[4.2.1]non-3-en-9-one (10 g, 73 mmol), ethyleneglycol (12.3 ml, 220 mmol) and p-toluenesulphonic acid monohydrate (100 mg) in toluene (250 ml) was refluxed in a Dean-Stark apparatus for four hours. The reaction mixture was cooled to ambient temperature and sequentially washed with water (3×50 ml) and brine (100 ml). The organic extract was dried over MgSO4 and concentrated in vacuo, to afford spiro[bicyclo[4.2.1]non-3-ene-9,2′-[1,3]dioxolane] (13.12 g, 99.5%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([S:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[S:28][CH2:29][C:30]([OH:32])=O)[CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=1)([CH3:10])[CH3:9].[CH3:33][NH:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:20][C:17]([C:15]1[CH:14]=[C:13]([S:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[S:28][CH2:29][C:30]([N:34]([CH3:33])[CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[O:32])[CH:12]=[C:11]([C:8]([CH3:10])([CH3:9])[CH3:7])[CH:16]=1)([CH3:19])[CH3:18]
Reactant: CNCCc1ccccn1
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
Oxalyl chloride (0.19 g, 0.0015 moles) was added by syringe to a cold (10° C.) solution of trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]acetic acid (0.55 g, 0.0014 moles) in benzene (50 ml). The cold bath was removed and the reaction mixture was stirred at room temperature for hours. The reaction mixture was concentrated to an oil (rotary evaporator). The oil was dissolved in toluene (50 ml) and concentrated to an oil. The process was repeated using tetrahydrofuran (25 ml) instead of toluene. The residue was dissolved in tetrahydrofuran (50 ml). To this solution was added 2-(2-methylaminoethyl)pyridine (0.19 g, 0.0014 moles) and triethylamine (0.22 g) and the reaction mixture was stirred at room temperature for 48 hours. The white solid precipitate was removed by filtration and washed with ethyl acetate (25 ml). The filtrate was concentrated to give the crude product as an oil. The product was purified by silica gel chromatography and dried in vacuo at 100° C. for 1 hour to give the title compound. The structure assignment was supported by NMR, infrared spectroscopy and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[C:12](=[CH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.[H][H]>CO.[C].[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CC(=CC2CCOCC2)C1=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: Cc1cc(Br)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O

Procedure:
A solution of 2-(4-bromo-2,6-dimethylphenyl)-4-[1-(tetrahydropyran-4-yl)methylidene]cyclopentane-1,3-dione (0.10 g, 0.26 mmol) in methanol (100 ml) is passed over a cartridge of 10% platinum carbon under a 20 bar hydrogen atmosphere. The reaction mixture is then concentrated in vacuo, and the crude product is purified by flash column chromatography (hexane/ethyl acetate as eluant) to afford rac-2-(4-bromo-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:8]2=[O:14].[C:22]1([C:28]2[CH:32]=[C:31]([CH:33]=O)[O:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:33][C:31]3[O:30][N:29]=[C:28]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:32]=3)[CH2:18][CH2:17]1)[C:8]2=[O:14]
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: O=c1c2ccc(Cl)c(Cl)c2ccn1CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1c2ccc(Cl)c(Cl)c2ccn1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
The compound prepared in Example 77 (0.041 g), the compound prepared in Example 7 (0.026 g) and sodium triacetoxyborohydride (0.074 g) were suspended in dichloromethane (5 mL) and diisopropylethylamine (0.10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:1) to obtain the title compound (0.029 g) having the following physical data.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[CH:6]=[C:5]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([NH:33][CH2:32][CH2:31][NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[C:12]=3[F:14])[C:7](=[O:18])[CH:6]=[C:5]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(=O)c2c(F)c(F)c(F)c(F)c2n1C1CC1
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(=O)c2c(F)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A solution ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-2-carboxylate (688 mg, 2.09 mmol), N-2-pyridyl-1,2-ethanediamine (570 mg, 4.16 mmol) and triethylamine (0.87 mL, 6.24 mmol) in DMSO (20 mL) was stirred at 70° C. After 1 h, the reaction mixture was poured into ice water and the resulting solution was extracted with EtOAc, and the organic layer washed with water, brine, and then dried. The solvent was removed and the crude product was purified by column chromatography (Hexane:EtOAc 1:1) to yield ethyl 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (773 mg, 83%) as yellow solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]([F:17])([F:16])[O:12][CH2:13][CH2:14][OH:15]>>[F:10][C:11]([F:17])([F:16])[O:12][CH2:13][CH2:14][O:15][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCCOC(F)(F)F
Reactant: N#Cc1ccc(Br)nc1
Product: N#Cc1ccc(OCCOC(F)(F)F)nc1
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (509 mg, colorless oil) from 6-bromonicotinonitrile (422 mg, 2.31 mmol) and 2-(trifluoromethoxy)ethanol (300 mg, 2.31 mmol) by the similar manner in Step-1 of Amine-101.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:13])[CH2:11][NH2:12])[CH:5]=[CH:4][N:3]=[CH:2]1.I.CS[C:17]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[N:18]=1>C(O)C>[N:18]1[C:19]2[C:24]3[C:23](=[CH:28][CH:27]=[CH:26][C:25]=3[C:17]=1[NH:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:13])[CH:22]=[CH:21][CH:20]=2
Reactant: NCC(=O)NCCCn1ccnc1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: I
Solvent: CCO
Product: O=C(CNC1=Nc2cccc3cccc1c23)NCCCn1ccnc1
Yield: 43.2 %

Procedure:
A mixture of 3.7 g of N-[3-(1H-imidazol-1-yl)propyl]glycinamide, 425 ml of ethanol, and 5.0 g of 2-(methylthio)benz[cd]indole hydroiodide was reacted as described in Example 19, giving 2.2 g of the desired product, mp 145°-146° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[OH:22][C:7]1[C:8]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:13][C:9]=2[C:10]([CH3:12])=[N:11][C:6]=1[C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 7-hydroxy-4-methyl-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (159 mg, 0.51 mmol) and glycine (760 mg, 1.01 mmol) in 0.5 M sodium methoxide/methanol (19.2 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (50 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (12 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (127 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.01 (br s, 1H), 9.24 (br s, 1H), 8.14 (m, 2H), 7.62 (m, 3H), 4.03 (d, J=6.2 Hz, 2H), 2.87 (s, 3H); MS: (+) m/z 344.0 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:18]1[C:22]([C:23]2[C:28]([CH3:29])=[CH:27][N:26]=[C:25](Cl)[N:24]=2)=[CH:21][C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]([NH2:17])[C:25]2[N:24]=[C:23]([C:22]3[S:18][C:19]4[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=4[CH:21]=3)[C:28]([CH3:29])=[CH:27][N:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccccc2s1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(C(N)CCN2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cc2ccccc2s1
Yield: 70.9 %

Procedure:
4-(3-Aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (261 mg, 1.07 mmol) is added to a stirred suspension of 4-(benzo[b]thiophen-2-yl)-2-chloro-5-methyl-pyrimidine (140 mg, 0.537 mmol) and diisopropylethylamine (140 μL, 0.805 mmol) in anhydrous 1,4-dioxane (3.5 mL) at ambient temperature under nitrogen. The resultant mixture is heated in an oil bath at 95° C. for 36 hours. At ambient temperature the mixture is concentrated and chromatographed on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 0-6%, to give 4-{3-[4-(benzo[b]thiophen-2-yl)-5-methyl-pyrimidin-2-yl]-amino-propyl}-piperazine-1-carboxylic acid tert-butyl ester as a white solid (178 mg, 70% yield).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([NH2:30])(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1>[C:15](=[S:2])([NH2:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCC(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(N)=S
Yield: 105.6 %

Procedure:
Phosphorus pentasulfide (9.8 g, 0.044 mol) was added to a mixture of tetradecanamide (8.6 g, 0.04 mol) in dry THF (250 mL) and the mixture refluxed overnight, concentrated in vacuo, and heated with methanol (200 mL), filtered, and the filtrate concentrated in vacuo to yield a pale yellow solid (10.28 g, 99%) used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]([CH3:41])=[C:39]2[S:42][C:43]([Sn](CCCC)(CCCC)CCCC)=[CH:44][C:38]2=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:43]2[S:42][C:39]3[C:38](=[N:37][N:36]([CH3:35])[C:40]=3[CH3:41])[CH:44]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nn(C)c(C)c2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c2sc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc2nn1C
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 2,3-dimethyl-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole (265 mg, 0.601 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 90 minutes. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 20-30% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (108 mg, 68.0%). 1H NMR (400 MHz, DMSO-d6) ppm 1.49-2.04 (m, 8H), 2.45 (s, 3H), 3.84 (br s, 1H), 3.92 (s, 3H), 4.27 (br s, 1H), 4.35-4.51 (m, 2H), 7.08 (d, J=6.06 Hz, 1H), 7.78 (br s, 3H), 8.60 (s, 1H), 9.25 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H23FN6OS, 415. found, 415.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]=1.[C:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)([OH:23])=[O:22].[OH-].[Na+]>CO>[O:18]=[C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH2:8][C:9]([CH3:20])([CH3:19])[C:10]=2[CH:11]=1)[CH:17]=[CH:28][C:27]1[CH:30]=[CH:31][C:24]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1cccs1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC=C(c2cccs2)c2ccc(C(=O)C=Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 62.6 mg (0.222 mmol) 3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-acetylnaphthalene (Compound D33) in 4.0 mL of MeOH were added 33.4 mg (0.222 mmol) of 4-carboxy benzaldehyde, and 240.0 mg (6.00 mmol; 2.0 mL of 3M aqueous NaOH). The resulting solution was stirred at room temperature for 12 h, concentrated under reduced pressure, and the residual oil dissolved in EtOAc. The solution was treated with 10% HCl, and the organic layer washed with H2O, and saturated aqueous NaCl, before being dried over Na2 SO4. Removal of the solvents under reduced pressure gave the title compound as a pale green solid after recrystallization from EtOH.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([NH:14][C@@H:15]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]([CH3:32])[C:16]2=[O:33])=[O:13])[CH:6]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH3:32][N:17]1[C:18]2[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=2[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:21][C@@H:15]([NH:14][C:12]([NH:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[O:13])[C:16]1=[O:33]
Reactant: COC(=O)Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](NC(=O)Nc2cccc(CC(=O)O)c2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (1.92 g, 4.47 mmol) was dissolved in THF (25 ml) and treated with a solution of (3-aminophenyl)acetic acid methyl ester (670 mg, 4.06 mmol) in THF (5 ml) followed by triethylamine (615 mg, 6.09 mmol). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue was treated with water (20 ml) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1M NaOH, then with 10% citric acid, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:1 hexane:ethyl acetate. The product fractions were combined and evaporated to dryness in vacuo and the residue crystallized from ethyl acetate to give (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenyl acetic acid methyl ester. This ester (885mg, 1.94mmol) was dissolved in THF (5 ml) and treated with a solution of lithium hydroxide (815 mg, 19.4 mmol) in water (10 ml). The mixture was stirred at ambient temperature for 3 hours, diluted with water (100 ml), acidified with 1N HCl, and extracted with ethyl acetate. The ethyl acetate layers were washed with brine, dried over sodium sulfate, filterate, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with chloroform followed by 9:1 chloroform:methanol. The product fractions were combined and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate to provide the title compound: (mp 167°-170° C.).
Reaction SMILES: [CH:1]1([CH:4]([OH:16])[CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1CCC(O)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.5 g of 1-cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (2.26 mmol), 0.26 g of triethylamine (2.6 mmol) and 12 ml of dichloromethane is cooled to a temperature of 5° C. and 0.28 g of methanesulfonic acid chloride, dissolved in 3 ml of dichloromethane, is added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1-Cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=1[CH3:37]>N1C=CC=CC=1.CCOC(C)=O>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([O:36][C:12]2[NH:11][C:10]3[CH:18]=[C:19]([F:20])[C:7]([C:4]4[CH:5]=[CH:6][C:1]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:2][CH:3]=4)=[CH:8][C:9]=3[N:13]=2)[CH:33]=[CH:32][C:31]=1[CH3:37]
Reactant: COC(=O)c1cc(O)ccc1C
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)ccc1C

Procedure:
To a solution of 7 (454 mg, 1.2 mmol) in pyridine 10 mL was added 5-hydroxy-2-methyl-benzoic acid methyl ester (412 mg, 2.4 mmol). The reaction mixture was heated to reflux for 5 days. Once the reaction was determined to be complete by TLC, the reaction mixture was diluted with EtOAc (100 mL) and washed two times with 100 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo to give a crude brown oil. The resulting oil was purified on ISCO (EtOAc/Hexanes=2/3) to give title compound 8 as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:7]2.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:7]2
Reactant: C1=COCCC1
Reactant: O=C(N1CCc2c(O)cccc2C1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCc2c(cccc2OC2CCCCO2)C1)C(F)(F)F

Procedure:
3.7 g (15.9 mmol) of 5-hydroxy-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (Example 1) and 4.4 mL (47.7 mmol) 2,3-dihydropyrane were dissolved in dichloromethane and catalytic amount of p-toluenesulfonic acid monohydrate was added. After completion of the reaction (System A), the reaction mixture was diluted with dichloromethane, washed with water and aqueous sodium chloride. The solution was dried over Na2SO4, evaporated to dryness, and the product was purified by silicagel chromatography (System A). Yield 4.13 g, 79%. 1H NMR (CDCl3, 400 MHz): 7.16 (1H, m), 7.00 (1H, m), 6.77 (1H, m), 5.45 (1H, m), 4.79 (2H, ss), 3.8 (3H, m), 3.6 (1H, m), 2.9 (4H, m).