Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[C:13]2[C:5]([CH2:6][CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][C:3]=1[OH:16].C[CH2:18][O:19]C(C)=O>C(C(C#N)=C1C=C(C=CC2C=CC(N(C)C)=CC=2)OC(C)=C1)#N.[Ti](Cl)(Cl)(Cl)Cl>[OH:16][C:3]1[C:2]([CH3:1])=[C:14]([CH3:15])[C:13]2[O:12][C:8]3([CH2:9][CH2:10][CH2:11]3)[CH2:7][CH2:6][C:5]=2[C:4]=1[CH:18]=[O:19]
Reactant: CCOC(C)=O
Reactant: Cc1c(O)cc2c(c1C)OC1(CCC1)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC1=CC(=C(C#N)C#N)C=C(C=Cc2ccc(N(C)C)cc2)O1
Product: Cc1c(C)c2c(c(C=O)c1O)CCC1(CCC1)O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
0.3 g of a solution of 7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (prepared as described herein) was dissolved in 20 mL of 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran (DCM). The solution was flushed with Argon then cooled to 0° C. in an ice bath. 0.151 mL (1.4 mmol) of titanium tetrachloride was added followed by 0.149 mL (1.7 mmol, 1.2 eq) of α,α-dichloromethyl-methyl ether. The solution was stirred at 0° C. for 10 min, warmed to room temperature, and stirred overnight. After addition of EtOAc (50 mL), the solution was washed with water, and then dried over Na2SO4. The crude material was purified on a silica column eluting with 1:8 EtOAc/hexane to yield 180 mg of 6-hydroxy-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-5-carbaldehyde as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=1.65-1-70 (m, 1H), 1.80-1.97 (m, 2H), 2.06-2.27 (m, 11H), 3.06-3.11 (t, 2H), 10.20 (s, 1H), 12.13 (s, 1H) ppm. MS (m/z)=247 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: CCO
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)c(F)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2ccc(F)cc2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To the suspension of 4-(2,4-difluoro-phenyl)-1H-indole (6.42 g, 28 mmol) in t-BuOH:ethanol:acetic acid (177 mL:105 mL:55 mL) was added pyridinium tribromide (27 g, 84 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (136 mL). Zinc dust (9.8 g, 150 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), neutralized with 1N HCl, washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 5.16 g (75%) of 4-(2,4-difluoro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: B(Br)(Br)Br.[ClH:5].C[O:7][C:8]1[CH:39]=[CH:38][C:11]2[C@@H:12]3[C@H:16]([CH2:17][CH2:18][C:10]=2[CH:9]=1)[N:15]=[C:14]([NH:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:23][CH2:22]1)[CH2:13]3.C(N(CC)CC)C.CO>ClCCl>[ClH:5].[OH:7][C:8]1[CH:39]=[CH:38][C:11]2[C@@H:12]3[C@H:16]([CH2:17][CH2:18][C:10]=2[CH:9]=1)[N:15]=[C:14]([NH:19][CH2:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([CH2:27][NH:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:25][CH2:26]1)[CH2:13]3
Reactant: COc1ccc2c(c1)CC[C@@H]1N=C(NC[C@H]3CC[C@H](CNS(=O)(=O)c4ccccc4)CC3)C[C@H]21
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC[C@H]1CC[C@H](CNC2=N[C@H]3CCc4cc(O)ccc4[C@H]3C2)CC1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of boron tribromide (3.4 mmol) in dichloromethane (3.4 mL) was added to a solution of N-[[trans-4-[[(cis-3a,4,5,9b-tetrahydro-7-methoxy-1H-benz[e]indol-2-yl)amino]methyl]cyclohexyl]methyl]benzenesulfonamide hydrochloride (8) (0.37 g, 0.714 mmol) and triethylamine (0.235 mL, 1.69 mmol) in dichloromethane (20 mL) at 0° C. The resultant mixture was stirred at 0° C. for 1 h, and stirring was continued at room temperature for an additional 1 h. The mixture was cooled on an ice bath and methanol was added. After stirring for several minutes, the solvents were evaporated In vacuo. The residue was purified by preparative HPLC on a C18 reverse phase column, eluted with waterlacetonitrile/trifluoroacetic acid (˜50:50:0.1). The product was dissolved in a minimum amount of methanol and converted to the hydrochloride salt with ethanolic hydrogen chloride. The solvents were evaporated in vacuo to give N-[[trans-4-[[(cis-3a,4,5,9b-tetrahydro-7-hydroxy-1H-benz[e]indol-2-yl)amino]methyl]cyclohexyl]methyl]benzenesulfonamide hydrochloride as a colorless solid (0.15 g, 42%). NMR (DMSO-d6): δ 0.67-0.98 (m, 4 H), 1.21-1.50 (m, 2 H), 1.58-1.97 (m, 6 H), 2.50-2.75 (m, 5 H), 3.03-3.23 (m, 2 H), 3.31-3.46 (m, 1 H), 3.55-3.67 (m, 1 H), 4.17-4.33 (m, 1 H), 6.53 (s, 1 H), 6.64 (d, 1 H), 6.99 (d, 1 H), 7.52-7.83 (m, 6 H), 9.34 (br s, 1 H), 9.76 (br s, 1 H) and 10.24 (br s, 1 H); MS 468 (M+H)+ (FIG. 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:33])[CH:9]([NH:25]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:25][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])=[CH:13][CH:12]=1)[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:33]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of tert-butyl (1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethylcarbamate (2.00 g, 4.05 mmol) in chloroform (20 ml) was added trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was basified with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure. The residue was recrystallized from (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol (1.08 g, 68%) as colorless crystals.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH3:20])[C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][N:22]=[C:23]=[O:24].CO.C(Cl)Cl>CCOC(C)=O.[Cu]Cl>[CH3:21][NH:22][C:23](=[O:24])[O:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([N:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH3:20])=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: CN(CCN1CCOCC1)c1noc2cc(O)ccc12
Reactant: CN=C=O
Agent: Cl[Cu]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(N(C)CCN3CCOCC3)noc2c1
Yield: 49.8 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol (2 g) and copper(I)chloride (0.3 g) in EtOAc (60 ml) was added methyl isocyanate (0.5 g). After 3.5 hours thin layer chromatography (TLC) (silica gel, 10% MeOH/DCM) showed no starting material. The reaction was filtered through neutral alumina eluting with EtOAc (2 l) and the filtrate was concentrated in vacuo to yield 1.2 g of the product, m.p. 94°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)([Cl:10])[Cl:9])[N:3]=1.CN1CCCC1=O.COP([O-])OC.[OH-].[Na+]>O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([Cl:10])[Cl:9])[N:3]=1
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Agent: COP([O-])OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: O
Product: Clc1cccc(C(Cl)Cl)n1
Yield: 81.4 %

Procedure:
In a stirred reaction vessel was placed 2.31 grams (0.010 mole) of 2-chloro-6-(trichloromethyl)pyridine, 20 ml of N-methylpyrrolidone and 1.35 grams (0.011 mole) of dimethylphosphite. The mixture was heated for about 21/2 hours. During this period, 50 percent aqueous sodium hydroxide was slowly added to maintain the pH slightly basic. At the end of the reaction period, there was 1% of the pyridine starting material remaining. Additionally, it was found that 0.0225 mole of the aqueous sodium hydroxide had been added. The reaction mixture was poured into water, extracted with methylene chloride, dried and the methylene chloride removed by evaporation, to yield 1.6 grams (80% of theoretical) of crude 2-chloro-6-(dichloromethyl)pyridine.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:17]([Br:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:24].[CH2:17]([N+:14]1[CH:15]=[CH:16][C:11]([C:2]([OH:1])([CH3:10])[C:3]2[CH:4]=[CH:5][C:6]([F:9])=[CH:7][CH:8]=2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(O)(c1ccncc1)c1ccc(F)cc1
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: CC(O)(c1ccc(F)cc1)c1cc[n+](Cc2ccccc2)cc1
Product: [Br-]

Procedure:
The starting material is prepared as follows: A mixture of 15 g of 4-(α-hydroxy-α-methyl-4-fluorobenzyl)- pyridine, 8.2 ml of benzyl bromide and 100 ml of acetonitrile is refluxed overnight. The solvent is evaporated and the residue recrystallized from isopropanol-diethyl ether, to yield the desired 1-benzyl-4-(α-hydroxy-α-methyl-4-fluorobenzyl)-pyridinium bromide melting at 175° with decomposition.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1cccc(F)c1F
Product: CN1CCCn2c1cc(OCCc1cccc(F)c1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(2,3-difluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[CH:11]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(C(C)(C)C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a solution of methyl 2-tert-butylquinoline-6-carboxylate (347 mg, 1.43 mmol) in MeOH (4 ml) and THF (4 ml) was added 2M aqueous sodium hydroxide (2 ml) at room temperature. The mixture was stirred at room temperature for 1.5 hours. Then evaporated, diluted with water (5 ml), neutralized to pH 5˜6 by 2M aqueous hydrochloride. The formed precipitate was collected, washed with water to furnish the title compound (282 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.49 (9H, s),7.62 (1H, d, J=8.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 8.31-8.34 (1H, m),8.64-8.66 (1H, m) MS (ESI): m/z 230 (M+H)+.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21](=[O:29])[O:20]1>>[CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:21](=[O:29])[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH2:19][OH:20])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2CO1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Product: O=C(Cc1ccccc1CO)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1

Procedure:
A solution of 0.256 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine and 0.148 g of 3-isochromanone was heated in a 126° C. oil bath for 17 hr. The residual materials were purified by silica gel chromatography using ethyl acetate-hexane (1:4 v/v) as the eluant to yield (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzyl alcohol.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([N:15]1[C@@H:20]2[CH2:21][CH2:22][C@@:16]1([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C@H:17]([OH:23])[CH2:18][CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:31][C:32]([F:46])([F:45])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:36]Br>CCCC(C)C.O>[CH2:8]([N:15]1[C@@H:20]2[CH2:21][CH2:22][C@@:16]1([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[C@H:17]([O:23][CH2:36][C:35]1[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=[C:33]([C:32]([F:31])([F:45])[F:46])[CH:34]=1)[CH2:18][CH2:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc([C@]23CC[C@H](CC[C@H]2OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
Sodium hydride (320 mg, 60% in oil, 7.98 mmol) was washed with iso-hexane (×3) then THF (8 ml) and (1R*,2R*,5R*)-8-benzyl-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 15; 1.24 g, 3.99 mmol) added and the mixture stirred at room temperature for 10 minutes then 3,5-bis(trifluoromethyl) benzyl bromide added and the reaction mixture stirred at 60° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [5% ethyl acetate in iso-hexane] to give the title compound (1.51 g, 58%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15]>O>[Cl:1][S:2]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:6][C:7](=[O:15])[CH2:8]2)(=[O:5])=[O:3]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
To a 100 mL flask charged with 27 mL of chlorosulfonic acid was added slowly 13.3 g of 2-oxindole. The reaction temperature was maintained below 30° C. during the addition. After the addition, the reaction mixture was stirred at room temperature for 1.5 hr, heated to 68° C. for 1 hr, cooled, and poured into water. The precipitate was washed with water and dried in a vacuum oven to give 11.0 g of 5-chlorosulfonyl-2-oxindole (50% yield) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[CH:13]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[C:13][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: C#CCN(C)C
Reactant: Nc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)CC#Cc1cncc(N)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a degassed solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol) and N,N-dimethylprop-2-yn-1-amine (1.57 mL, 14.6 mmol) in TEA (26 mL) were added bis(triphenylphosphine)palladium(II) chloride (0.203 g, 0.29 mmol) and copper iodide (0.110 g, 0.58 mmol). The reaction mixture was allowed to stir under an atmosphere of argon at 80° C. for 14 h. The reaction mixture was allowed to cool to rt and then filtered through Celite. The filter pad was washed with EtOAc and the filtrate was concentrated. The residue was purified by column chromatography to give 5-[3-(dimethylamino)prop-1-yn-1-yl]pyridin-3-amine (0.55 g, 54%).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.N1CCCCC1.[F:24][C:25]([F:29])=[C:26](F)F.CN(C)C=[O:33]>>[F:24][CH:25]([F:29])[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:33]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: CN(C)C=O
Reactant: FC(F)=C(F)F
Solvent: C1CCNCC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 21 h
Yield: 74 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and piperidine (0.64 g, 7.5 mmol) in N,N-dimethylformamide (10 ml) was reacted in a reaction flask with tetrafluoroethylene, which was made to flow into the flask (ca. 0.7 liter/hr), with vigorous stirring at 50° C. for 21 hours. After cooling to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with diethyl ether. The diethyl ether layer was washed with water and then brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.24 g, 3.7 mmol, yield 74%). Unreacted part of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.30 g) was recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12](C(=N)NOC(OCC)=O)[CH:11]=2)[C:7]2[C:31]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH3:2].[N:39]12CCC[N:46]=[C:45]1CCCCC2.[C:50]([O:53]CC)(=[O:52])C>>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:45]3[NH:46][O:53][C:50](=[O:52])[N:39]=3)=[CH:14][CH:15]=2)[C:7]2[C:31]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)ONC(=N)c1cc(Cn2c(OCC)nc3cccc(C(=O)OC)c32)ccc1-c1ccccc1
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
The crude crystals (4.0 g) obtained in Example (57b) was dissolved in ethyl acetate (50 ml). To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.2 g), and the mixture was stirred for 2 hours at 80° C. The reaction mixture was partitioned between ethyl acetate (50 ml) and 1N HCl (20 ml). The organic layer was washed with water, dried and concentrated to dryness. The residue was crystallized from chloroformethyl acetate to afford the title compound as colorless prisms (2.1 g, 45%), which was in agreement with that obtained in Example (1d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[CH:50][C:43]=23)[CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:48]1[C:44]2=[N:45][CH:46]=[N:47][C:42]([NH:41][C@H:37]3[CH2:38][CH2:39][CH2:40][N:35]([C:11](=[O:13])[CH2:10][NH:9][C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:36]3)=[C:43]2[CH:50]=[N:49]1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: c1nc(N[C@H]2CCCNC2)c2cn[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCC[C@H](Nc2ncnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a cooled solution of 2-(3,5-dichlorophenylamino)acetic acid (102 mg, 0.45 mmol) at 0° C. in anhydrous DMF (5 mL), HOBt (135 mg, 0.68 mmol) was added and the reaction mixture was stirred for 10 min before EDCI (132 mg 0.68 mmol), (S)—N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.45 mmol) and DIEA (117 mg, 0.90 mmol) were added in succession. The reaction mixture was allowed to warm to rt and stirred overnight. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with EtOAc (50 mL) and was washed with water (3×20 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled intermediate (62 mg, 32%). 1H NMR (400 MHz, CDCl3): δ 11.42 (bs, 1H), 8.58 and 8.49 (2s, 1H), 7.98 (s, 1H), 6.71 and 6.68 (2s, 2H), 6.41 and 6.39 (2s, 2H), 5.29-5.18 (m, 1H), 4.40-4.09 (m, 2H), 3.94-3.42 (m, 3H), 3.18-3.03 (m, 1H), 2.27-2.20 (m, 1H), 1.97-1.56 (m, 4H). LC-MS: m/z [M+1]=420.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([N:12]=[N+]=[N-])=[CH:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH:6]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=Cc1cccs1)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc2sccc2[nH]1
Yield: 80 %

Procedure:
The resulting azide, 2-azido-3-thiophen-2-yl-acrylic acid ethyl ester (650 mg, 2.88 mmol) was dissolved in toluene (40 ml) and the solution was refluxed for 2 hours. The solution was thereafter cooled, and water (80 ml) was added. After separation of the phases the aqueous phase was extracted with ethyl acetate (3×20 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 450 mg of pure 4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (80% yield).
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([O:28][C:29]([NH:31][C@@H:32]1[CH2:36][O:35][NH:34][C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]1[CH2:36][O:35][N:34]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
In 2 ml of dichloromethane were dissolved 85 mg of Compound (1) and 60 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added 77 mg of 2-chloro-1-methylpyridinium iodide and 84 μ1 of triethylamine. The mixture was stirred at room temperature for 40 minutes, followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, followed by conducting workup similar to that in Example 8(a) to give 31 mg of the subject Compound (8).
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[N-:18]=[N+:19]=[N-:20].[Na+].O>CS(C)=O>[N:18]([CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N+:19]=[N-:20]
Reactant: O=C1Nc2ccc3ccccc3c2CCC1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC1CCc2c(ccc3ccccc23)NC1=O
Temperature: 60 °C

Procedure:
To a suspension of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H- naphtho-[2,1-b]azepine (16.6 g, 67.6 mmol) in DMSO (80 ml) was added sodium azide (8.8 g, 135 mmol) and the suspension was heated at 60° C. for 5 h. The hot reaction mixture was poured into water (1 L). The precipitate was isolated by filtration and washed with water. After drying in vacuo 16.3 g of 3-azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine was obtained.