Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.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]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Reactant: COc1ccc(B(O)O)cc1OC
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: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1OC
Temperature: 120 °C

Procedure:
1-Benzenesulfonyl-3-bromoindole 20 (350 mg, 1.0 mmol) was dissolved in tetrahydrofuran (6 mL). Into the solution was added 3,4-dimethoxyphenyl boronic acid (379 mg, 2.1 mmol), tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) and 1 M potassium carbonate (3 mL). The reaction mixture was heated in a CEM Discover microwave instrument at 120° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure and partioned between ethyl acetate and saturated sodium bicabonate. The organic portion was dried over anhydrous magnesium sulfate, and filtered. The filtrate was adsorbed onto silica gel and purified by flash chromatography (5%-50% ethyl acetate:hexanes) to provide the desired product, 19, (359 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH:24]1[CH:28]=[N:27][C:26]([CH2:29][N:30]2[C:34](=[O:35])[CH2:33][S:32][C:31]2=[O:36])=[N:25]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:33]4/[C:34](=[O:35])[N:30]([CH2:29][C:26]5[N:27]=[CH:28][NH:24][N:25]=5)[C:31](=[O:36])[S:32]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:21])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C1CSC(=O)N1Cc1nc[nH]n1
Product: O=C1S/C(=C\c2ccc3c(c2)nnn3Cc2ccc(Cl)cc2C(F)(F)F)C(=O)N1Cc1nc[nH]n1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-(1H-1,2,4-triazol-3-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(1H-[1,2,4]triazol-3-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 90) following General Procedure F.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[C:27]([C:28](N)=[O:29])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:33][N:34]([CH2:36][C:37]([N:39]1[C:48]2[C:43](=[CH:44][C:45]([O:50][CH3:51])=[C:46]([NH2:49])[CH:47]=2)[CH2:42][CH2:41][CH2:40]1)=[O:38])[CH3:35].Cl.O1CCOCC1.[I-].[K+]>FC(F)(F)CO.ClCCl.C(=O)(O)[O-].[Na+]>[CH3:35][N:34]([CH3:33])[CH2:36][C:37]([N:39]1[C:48]2[C:43](=[CH:44][C:45]([O:50][CH3:51])=[C:46]([NH:49][C:2]3[N:3]4[C:4](=[N:21][C:22]5[C:27]([C:28]4=[O:29])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)[CH:47]=2)[CH2:42][CH2:41][CH2:40]1)=[O:38]
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(F)c(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CCC2
Temperature: 90 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a suspension of 6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluorobenzamide (600 mg, 1.26 mmol) in 2,2,2-trifluoroethanol (40 ml) was added 1-[(dimethylamino)acetyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (366 mg, 1.39 mmol), hydrochloric acid as a 4.0M solution in dioxane (2.51 ml, 10.1 mmol), and catalytic potassium iodide (<10 mg). The resulting slurry was stirred at 90° C. in a pressure vial for 24 hours, at which time all solids had completely dissolved. The resulting solution was cooled to room temperature and diluted with dichloromethane and saturated sodium bicarbonate as to adjust the aqueous layer to pH>10. The organic layer was washed with water and a saturated brine solution, dried over sodium sulfate, filtered and solvents were removed under reduced pressure. The resulting green solid was purified via trituration with diethyl ether to afford 5-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (830 mg, 1.21 mmol) as a yellow solid. (ESIMS (M+H)+=688)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].Cl.[Cl:24][S:25](O)(=[O:27])=[O:26]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3ccccc32)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(S(=O)(=O)Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
(0.04 mol) of 1-[3-(4-cyano-phenyl)-propionyl]-1,2,3,4-tetrahydro-quinoline are dissolved in 16 ml of chlorosulphonic acid at 0° C. The thickly liquid mass is heated to 60° C. and hydrochloric acid develops. Then the mixture is carefully added to ice and extracted with methylene chloride, dried and concentrated by rotary evaporation.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:21](O)=[O:22])[CH3:20])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].O=S(Cl)Cl.[NH2:28][C:29]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][C:30]=1[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C([O-])(O)=O.[Na+]>C(O)C.C(Cl)(Cl)Cl>[C:31]([C:30]1[CH:39]=[C:40]([N+:43]([O-:45])=[O:44])[CH:41]=[CH:42][C:29]=1[NH:28][C:21](=[O:22])[CH:19]([NH:18][C:1](=[O:2])[O:3][CH2:4][CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:20])(=[O:32])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Temperature: 50 °C
Yield: 98 %

Procedure:
Commercially-available (S)-Fmoc-alanine (2.98 g, 0.96 mmol) was suspended in ethanol-free CHCl3 (30 mL) and SOCl2 (7 mL) was added under N2. The mixture was heated at 50° C. for 1 h, then the solvent was removed under vacuum, the residue was dissolved into CHCl3 (30 mL), commercially-available 2-amino-5-nitro-benzophenone (2.32 g, 0.96 mmol) was added, and the mixture was heated for 2 h at 60° C. After cooling, a saturated solution of NaHCO3 was added, the organic phase was collected and dried (Na2SO4), then the solvent was removed under vacuum obtaining (9H-fluoren-9-yl)methyl 1-(2-benzoyl-4-nitrophenylamino)-1-oxopropan-2-ylcarbamate (98% yield). This compound was dissolved in CH2Cl2 (40 mL), Et3N (10 mL) was added and the mixture was heated at 40° C. for 30 h under N2. The solvent was removed under vacuum and the residue was partitioned between 2N HCl and ethyl acetate; the aqueous layer was made alkaline with 10% NaOH and extracted with CH2Cl2. After drying (Na2SO4) and removal of solvent, the residue was purified by flash chromatography (cyclohexane/ethyl acetate 6:4 as eluent) yielding (S)-3-methyl-7-nitro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one in 25% yield.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[O:21]1[CH2:26]CO[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH2:22]([O:21][CH2:26][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1)[CH3:23]
Reactant: C1COCCO1
Reactant: Nc1ncccc1-c1cnn(Cc2ccc(Br)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCc1ccc(Cn2cc(-c3cccnc3N)cn2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 17 %

Procedure:
To a mixture of 3-(1-(4-bromo-benzyl)-1H-pyrazol-4-yl)-pyridin-2-ylamine (24 mg, 0.073 mmol) described in Manufacturing Example 195-1-1 and 1,4-dioxane (1.5 mL) were added water (150 μL), cesium carbonate (95 mg, 0.29 mmol), the potassium ethoxymethyl trifluoroborate (18 mg, 0.11 mmol) described in Manufacturing Example 196-1-2, palladium(II) acetate (1.6 mg, 0.0073 mmol), and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.5 mg, 0.0073 mmol) at room temperature, which was stirred under nitrogen atmosphere for 6 hours at 100° C. The reaction mixture was cooled to room temperature, after which water and ethyl acetate were added and the mixture was filtered through a Celite pad. The organic layer of the filtrate was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.2 mg, 17%) as a trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][CH2:5][C:6]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:7]=1[Cl:13].[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(N(CC)CC)C.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>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][C:6]=1[CH2:5][NH:4][C:3](=[O:14])[O:2][CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)NCc1cc(I)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(C#C[Si](C)(C)C)ccc1Cl

Procedure:
A mixture methyl[(2-chloro-5-iodo-phenyl)methyl]carbamate (i.e. the product of Step B) (3.0 g, 9.2 mmol), ethynyltrimethylsilane (1.94 mL, 13.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.032 g, 0.05 mmol), copper(I) iodide (0.018 g, 0.09 mmol), triphenylphosphine (0.024 g, 0.09 mmol) in tetrahydrofuran (18 mL) and triethylamine (18 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated onto silica gel (7 g) and then purified by medium pressure liquid chromatography (0 to 25% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as an oil (1.37 g).
Reaction SMILES: CO.[ClH:3].[NH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17]CC3C=CC=CC=3)[C:11]=2[C:15]#[N:16])[C@H:6]1[OH:25]>[H][H].[Pd]>[ClH:3].[NH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:17])[C:11]=2[C:15]#[N:16])[C@H:6]1[OH:25]
Reactant: N#Cc1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N#Cc1c(O)ccc2c1CC[C@@H](N)[C@@H]2O

Procedure:
In 20 ml. of methanol is dissolved 200 mg. of trans-2-amino-6-benzyloxy-5-cyano-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride, followed by the addition of 30 mg. of 5% palladium-on-carbon. The mixture is agitated in hydrogen streams at room temperature for 30 minutes. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is recrystallized from methanol-ethyl acetate. The procedure yields white crystals of trans-2-amino-5-cyano-1,6-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride. Yield 136 mg.; melting point: 259°-261° C(decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:36][C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44].COC1C=C(C2C(C)(C)C(=O)N(C3CCN(S(C4C=C(OC)C=CC=4OC)(=O)=O)CC3)N=2)C=CC=1OC.[OH-].[Na+]>C(O)C>[Cl:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:44])[C:37]=1[CH2:36][O:30][C:28]1[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:23])[CH:29]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Agent: COc1ccc(OC)c(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5c(Cl)cccc5Cl)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 0.40 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.41 g 2-(bromomethyl)-1,3-dichlorobenzene in 5 ml ethanol is treated with 0.17 ml 10 n aqueous sodium hydroxide solution and stirred under a blanket of nitrogen for about 6 h at 80° C. until the reaction is completed largely according to TLC analysis. The solvent is evaporated under reduced pressure, and the resulting crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH2:39][CH2:40][CH2:41][NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[N:34]1([CH2:39][CH2:40][CH2:41][NH:42][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NCCCN1CCCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCCN1CCCC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 3-pyrrolidin-1-yl-propylamine to give the titled compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2cccs2)nc1
Temperature: 25 °C
Yield: 290.5 %

Procedure:
2-thienylboronic acid (Lancaster Synthesis, Inc., 1.00 g, 7.81 mmol), 2-chloro-5-trifluoromethylpyrdine (Adrich Chemical Co., 1.417 g, 7.81 mmol), tetrakistriphenylphosphine palladium(0) (Aldrich, 451 mg, 0.391 mmol), potassium carbonate (EM Science, 3.24 g, 23.4 mmol), water (20 mL), and dimethoxyethane (Aldrich, 20 mL) were allowed to stir at reflux for 20 hours under N2, after which time the mixture was cooled to room temperature and the organic and aqueous layers were separated. The aqueous layer was extracted with 3×50 mL of diethyl ether, and the combined organic fractions were dried with sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel flash chromatography with CH2Cl2/hexanes (1:1) as the eluent (product Rf=0.5), to afford the product as a white crystalline solid (yield=5.2 g, 73% isolated yield). 1H NMR (CDCl3, 296 K, 300 MHz): δ=7.73-7.57 (2H, m), 7.55 (1H, d, J=8.5 Hz), 7.34 (1H, d, J=4.8 Hz), 6.88 (1H, d, J=4.8 Hz) ppm. 19F NMR (CDCl3, 296 K, 282 MHz) δ=−62.78 ppm. Intermediate bridged dimer,
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1S(=O)(=[O:17])CCC1.[OH-].[K+].Cl>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:17])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: O=S1(=O)CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 110 °C
Reaction time: 21 h
Yield: 75.8 %

Procedure:
384 g of 2,4-dichloronitrobenzene, 600 g of tetramethylene sulfone (sulfolane) and 1 g of the emulsifier as specified in Example 1 are introduced into the reaction vessel. Within 4 hours 448 g of 50% potassium hydroxide solution are added at 110° C. After stirring for a further 21 hours at 110° C., the reaction product is adjusted to pH 5.5 to 6 with 240 g of 30% hydrochloric acid and worked up as described in Example 1. 263 g of 5-chloro-2-nitrophenol (76% of the theory) are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21][C:7]=3[N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:9]=2[CH:10]=1.[F:32][C:33]([F:48])([F:47])[C:34]1[N:39]=[N:38][C:37]([C:40]2[CH:45]=[CH:44][NH:43][C:42](=[O:46])[CH:41]=2)=[CH:36][CH:35]=1>>[O:46]=[C:42]1[CH:41]=[C:40]([C:37]2[N:38]=[N:39][C:34]([C:33]([F:48])([F:47])[F:32])=[CH:35][CH:36]=2)[CH:45]=[CH:44][N:43]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:22][CH2:21][C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)ccc3c2C1
Yield: 30.7 %

Procedure:
tert-Butyl 7-bromo-5-(triisopropylsilyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (260 mg, 0.51 mmol) and 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (123 mg, 0.510 mmol) were reacted according to the procedure of Example 30 (step g) to provide the title compound (80 mg, 30%) as a yellow solid: ESI MS m/z 512 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][C:9]#[N:10].N>C(O)(C)C.[Ni]>[CH3:11][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: CN(C)CCCNCCC#N
Agent: [Ni]
Agent: N
Solvent: CC(C)O
Product: CN(C)CCCNCCCN

Procedure:
216 g of N,N-dimethyl-N'-(β-cyanoethyl)-1,3-diaminopropane are hydrogenated in 216 ml of isopropanol in the presence of 140 g of gaseous ammonia and 13 g of Raney nickel in an autoclave at 120° C. and under an initial pressure of 80 atmospheres until the pressure remains constant, which is already the case after 30 minutes. The catalyst is filtered off with suction, the filtrate is concentrated in a rotary evaporator and the residue is distilled through a packed column. Yield: 205.7 g (92.8%); boiling point 121° C./11 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH:24]1[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1c[nH]c2ccccc12
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1c[nH]c2ccccc12

Procedure:
Intermediate 1 was coupled with 2-(1H-Indol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 518.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(NC(=O)[O-])C.O[C:29]1[C:30]([Cl:42])=[CH:31][C:32]2[CH:33]([CH3:41])[CH:34]3[CH2:38][NH:37][CH2:36][CH:35]3[C:39]=2[CH:40]=1>C(Cl)Cl>[Cl:42][C:30]1[CH:29]=[CH:40][C:39]2[CH:35]3[CH2:36][NH:37][CH2:38][CH:34]3[CH:33]([CH3:41])[C:32]=2[CH:31]=1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1c2cc(Cl)ccc2C2CNCC12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridine (0.23 mL, 2.85 mmol) and trifluoromethanesulfonic anhydride (0.32 mL, 1.90 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.28 g, 0.95 mmol) in CH2Cl2 (10 mL), and stirred for 1.5 hours at room temperature. The reaction was diluted with CH2Cl2 (10 mL), washed with H2O (10 mL), aqueous HCl (1.0 M, 10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic extract was dried over MgSO4 and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C16H17F3ClNO5S+H: 428, observed: 428.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:5]1[S:1][C:2]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[N:3][CH:4]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)OC(=O)Nc1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A solution of tert-butyl thiazol-2-ylcarbamate (15.0 g, 75 mmol), in THF (200 mL) was stirred at −78° C. and then n-butyl lithium (63 mL, 157 mmol) was added dropwise over 15 minutes. The resulting solution was stirred at −78° C. for 30 minutes, and then tributyltin chloride (22 mL, 82 mmol) was then added dropwise. The resulting pale yellow mixture was stirred for 30 minutes at −78° C. The bath was then removed, and the mixture was allowed to warm to room temperature. The reaction was then stirred for 2.5 hours. The reaction mixture was quenched with a saturated NH4Cl solution (300 mL). The layers were separated, and the aqueous layer was extracted with ether (3×100 mL). The organic layers were combined, washed with brine (300 mL), dried over MgSO4, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (330 g), eluting with a gradient of 10% to 20% EtOAc in hexanes, to provide the title compound (30 g, 81%) LCMS (M+H+) 490.1 calc. for C20H38N2O2SSn 490.1; 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (s, 1H), 1.59 (s, 9H), 1.30 (tt, 6H), 1.54 (t, 6H), 1.10 (qt, 6H), 0.80 (t, 9H).