Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Li]CCCC.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH3:1][CH:2]([CH3:5])[C:3]#[C:4][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C#CC(C)C
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
Under an Ar atmosphere, to a mixture of 3-Methylbutyne (1.5 g, 22.0 mmol) in THF (15 ml) was added a solution of 2.5 M n-BuLi in hexanes (9.68 ml, 24.2 mmol) at −78° C. over 15 min, then the mixture was stirred at −78° C. for 5 min, and at −5˜−10° C. for 30 min. Ethyl chloroformate (2.63 g, 24.2 mmol) was added drop wise at −78° C., then the mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated aqueous NH4Cl under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by kugelrohr distillation (1˜3 mmHg 70˜80° C.) gave 2b (59%). 2b: colorless oil; 1H-NMR (CDCl3) δ 1.24 (6H, d, J=7.0 Hz), 1.31 (3H, t, J=7.2 Hz), 2.70 (1H, sep, J=7.0 Hz), 4.22 (2H, q, J=7.2 Hz).
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:20][NH2:21]>CCO>[NH2:6][C:5]1[NH:21][N:20]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: NN
Reactant: CSC(Nc1ccc([N+](=O)[O-])cc1)=C(C#N)C#N
Solvent: O
Solvent: CCO
Product: N#Cc1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((methylthio)((4-nitrophenyl)amino)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq., 3.64 mL), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](I)[CH3:27]>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH3:27]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(C)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN([C@H](C(=O)OC)C(C)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound 9C (3 g, 8.94 mmol) dissolved in DMF (15 ml) was added with K2CO3 (1.1 equiv., 1.36 g) and ethyl iodide (1.1 equiv., 1 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 2.8 g of a semisolid. Yield=97%. 1HNMR (DMSO, 200 MHz) δ 1.00 (3H, d, J=6.2 Hz), 1.26 (3H, t, J=7 Hz), 3.32 (3H, s), 3.34 (2H, m), 4.02 (1H, bs), 4.23 (1H, m), 5.14 (1H, d, J=4.4 Hz), 7.62 (2H, m), 7.76 (2H, m)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].N1C=CN=C1.[C:16]1([Si:22](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][Si:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:23]([CH3:26])([CH3:24])[CH3:25])=[O:6]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC(=O)c1cccc(O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
To stirred solution of 50.4 g of 3-hydroxybenzoic acid in 200 ml of dry dimethylformamide at 0° C. was added 24.85 g of imidazole, followed by 100 g of diphenyl-(2-methylprop-2-yl)silyl chloride. The mixture was stirred at room temperature for 16 hours, and partitioned between ethyl acetate and cold water. The organic layer was washed with water, with an aqueous potassium hydrogen carbonate solution and with brine, was dried over anhydrous magnesium sulphate and evaporated to dryness. The resulting white solid was slurried in dry chloroform and filtered to afford 72 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:19]([NH:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CO>O>[Br:1][C:2]1[C:19]([NH:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CNc1nc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1nc2c(cc1Br)C(C)CNCC2
Yield: 54.7 %

Procedure:
A mixture of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -pyrido[2,3-d]azepin-2-ol (30.0 mg, 85.0 μmol), Tf2O (50 μl), K2CO3 (18 mg) and DCM (1 ml) was stirred for 16 h at room temperature. The mixture was extracted with sat. aq. NaHCO3, dried over Na2SO4, concentrated in vacuo and purified by column chromatography to yield 11.0 mg (26%) of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate. A mixture of methylamine (50 μl), 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate (11.0 mg, 22.7 μmol), and THF (1 ml) was heated to reflux for 15 h. The reaction mixture was parted between sat. aq. NaHCO3 and EtOAc. The organic layer was dried, concentrated in vacuo and purified with column chromatography to give 5.2 mg (62%) of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 486.2 (M+H+). A mixture of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine (5.2 mg, 14.2 μmol), K2CO3 (15 mg), MeOH (1 ml) and H2O (100 μl) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 2.1 mg (55%) of 3-bromo-N,5-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 271.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11].C([Li])CCC>>[F:1][C:2]1[C:3]([F:8])=[C:4]([Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:5]=[CH:6][C:7]=1[Si:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(F)c1F

Procedure:
4-Alkoxy-2-fluoro-3-phenoxyphenylacetic acid compounds were prepared from o-difluorobenzene. A mixture ortho-difluorobenzene (54a) and trimethylsilylchloride was treated with butyl lithium to produce 2,3-difluoro-1,4-bis-trimethylsilanyl-benzene (54b) which was brominated to afford 54c. Selective monometallation of 54c with iso-propylmagnesium chloride-lithium chloride complex and quenching the organomagnesium compound with DMF afforded 54d. Reaction of 54d with a phenol in the presence of K2CO3 resulted in displacement of the fluorine atom adjacent to the aldehyde to afford 56a. The aldehyde was subjected to a Baeyer-Villiger oxidation with trifluoroperacetic acid which underwent concomitant hydrolysis to the phenol 56b which was alkylated with Cs2CO3 and methyl iodide to afford the methoxy substituted analog 56c. Metallation of the remaining bromine substituent with iso-PrMgCl/LiI/THF and allylation of the resulting Grignard reagent afforded 58a which was oxidatively cleaved with NaIO4/Ru(III)Cl3 to produce the phenylacetic acid 58b.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[OH:27])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:29][C:30]1[CH:31]=[CH:32][C:33]2[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=2[CH:45]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=3[CH:45]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: C=CCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCOC)C(=O)CO3)cc1

Procedure:
Analogously to Method D, 20.0 g of benzyl 4-(4-allyloxyphenyl)-3-hydroxypiperidine-1-carboxylate and 15.6 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.20 (1:1 EtOAc-heptane); Rt=5.43.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[S:17][C:16](Br)=[C:15]([C:19]#[N:20])[C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](C)(C)[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I.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>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[S:17][C:16]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=2)=[C:15]([C:19]#[N:20])[C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: N#Cc1c(Br)sc(-c2nccn2Cc2ccccc2)c1-c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2sc(-c3nccn3Cc3ccccc3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Temperature: 90 °C
Yield: 59.5 %

Procedure:
5-(1-benzyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)thiophene-3-carbonitrile (107 mg, 0.219 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (85.0 mg, 0.284 mmol), Lithium chloride (30.0 mg, 0.708 mmol), Copper(I) iodide (4.70 mg, 0.0247 mmol) and Tetrakis(triphenylphosphine)palladium(0) (24.7 mg, 0.0214 mmol) were taken up in 1,4-Dioxane (3.0 mL) under an atmosphere of argon. The mixture was heated at 90° C. for 4 hours. The solvent was evaporated and the residue was purified using ISCO chromatography on silica gel, elution with 1-2% MeOH in DCM to give the product (0.071 g, 60%). LCMS: (FA) ES+ 544, 546. 1H NMR (400 MHz, d1-chloroform) δ: 8.59 (s, 1H), 8.40 (d, J=5.27 Hz, 1H), 8.03 (s, 1H), 7.52 (dd, J=5.27 Hz, 1.76 Hz, 1H), 7.30 (d, J=2.00 Hz, 1H), 7.27-7.16 (m, 6H), 6.87 (d, 1H), 6.77-6.75 (d, J=6.27 Hz, 2H), 4.90-4.78 (m, 2H), 2.25 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:21][S:18]([C:15]1[N:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cn1
Yield: 78.8 %

Procedure:
4-[6-(Methylsulfonyl)-3-pyridinyl]phenol was prepared as a brown solid from (4-hydroxyphenyl)boronic acid (0.34 g, 2.40 mmol), 5-bromo-2-(methylsulfonyl)pyridine (0.54 g, 2.29 mmol), 2M Na2CO3 (15 mL) and Pd(PPh3)4 (25 mg, 0.02 mmol) in DME (5 mL) in a manner similar to Example 1, Step 1. The crude product was triturated with 1:1 CH2Cl2/hexane to give 0.45 g (79%) of 4-[6-(methylsulfonyl)-3-pyridinyl]phenol as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 9.01 (d, 1H, J=2.2 Hz), 8.30 (dd, 1H, Ja=8.3 Hz, Jb=2.2 Hz), 8.02 (d, 1H, J=8.3 Hz), 7.66 (d, 2H, J=8.8 Hz), 6.90 (d, 2H, J=8.5 Hz), 3.27 (s, 3H); LRMS (APCI), m/z 250 (M+H).
Reaction SMILES: [F:1][C:2]([F:10])([CH2:5][CH2:6][CH2:7][O:8][CH3:9])[C:3]#[N:4].[CH:11]([Mg]Br)=[CH2:12].[BH4-].[Na+].Cl>O1CCCC1.CO.O>[NH2:4][CH:3]([C:2]([F:10])([F:1])[CH2:5][CH2:6][CH2:7][O:8][CH3:9])[CH:11]=[CH2:12]
Reactant: C=C[Mg]Br
Reactant: COCCCC(F)(F)C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(N)C(F)(F)CCCOC
Temperature: -12 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of nitrogen, 2,2-difluoro-5-methoxyvaleronitrile (4.85 mg, 3.25 mmoles), dissolved in tetrahydrofuran (5 ml), is slowly added to vinyl magnesium bromide (8 ml, 0.5M in tetrahydrofuran, 4 mmoles) previously cooled to -12° C. The reaction mixture is kept at -10° C. for 1/2 hour and then cooled to -40° C. A solution/suspension of sodium borohydride (133 mg, 3.5 mmoles) in methanol (14 ml) and water (0.5 ml), cooled to -40° C., is poured into the mixture, The temperature is allowed to rise to 0° C., and the mixture kept at this temperature for 10 min. The mixture is acidified with 6N HCl and concentrated under reduced pressure. The residue is dissolved in water, the aqueous solution is extracted twice to remove by-products, made alkaline with 4N NaOH, saturated with sodium chloride, and extracted again twice with ether. Usual work-up gives the title compound as a yellowish oil which is used for the next step without further purification: 420 mg (70)%.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].CN(CC1C=CC=CC=1)C.[C:22](Cl)(=[O:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:22](=[O:31])[CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)Cc1ccccc1
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
To a suspension of 86.5 g of anhydrous sulphanilic acid in 120 g of acetone are added dropwise, while stirring at 30° C., 168.8 g of N,N-dimethyl-benzylamine in the course of 15 minutes, followed by a solution of 83.5 g of cinnamoyl chloride in 80 g of acetone in the course of 50 minutes. After the addition is complete, the reaction temperature is increased to the reflux temperature for 1 hour, and the acetone is then removed as completely as possible. The residue which remains is stirred for 1 hour at 80° C., 90 g of 50% strength sodium hydroxide solution in 500 ml of water are then added, and the mixture is again heated to 80° C. and left to stand at this temperature for 15 minutes. The phases are separated and the aqueous phase is washed with 50 g of toluene. The aqueous phase, which is still hot, is diluted with 800 ml of water and neutralized with concentrated sulphuric acid. The cooled aqueous solution is then added dropwise in the course of 20 minutes to 1 kg of 50% strength sulphuric acid, while stirring vigorously. The precipitated crystals are separated off and dissolved in 4 liters of water, the solution is filtered, and again brought to crystallization by the addition of 100 g of concentrated sulphuric acid. 111 g of pure N-(p-sulfophenyl)-cinnamamide (corresponding to 75.9% of theory) with a melting point of 235°-237° C. are obtained. UV spectrum (in methanol):
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[C:21]=1[N+:28]([O-:30])=[O:29]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[C:21]=2[N+:28]([O-:30])=[O:29])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1F
Reactant: CNc1nccc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c(F)c2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 2-fluoro-4-hydroxyphenylcarbamate (3.25 g, 14.4 mmol) was dissolved in DMSO (25 mL) and the solution was stirred under an argon atmosphere for 20 minutes. Sodium hydride (60% in mineral oil, 580 mg, 14.4 mmol) was added portionwise and the dark solution was stirred at room temperature for 1 hour. 4-chloro-N-methyl-3-nitropyridin-2-amine (2.7 g, 14.4 mmol) dissolved in DMSO (5 mL) was added at once and the red solution was stirred at 50° C. for 2 hours. The solution was cooled, poured onto crushed ice (200 g) and extracted with ethyl acetate (3×100 mL). The organic phases were washed with brine, dried and evaporated to give the title compound as a yellow solid.
Reaction SMILES: C[C@:2]1([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34]C)=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.O.O.O.[F-:47].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:9][C:8]([F:11])([F:10])[C@H:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:3]1)[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][OH:34])=[C:26]([F:47])[CH:27]=4)[N:22]=3)=[N:19][N:20]=2)[CH:17]=1
Reactant: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a stirred solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.37 g, 1.94 mmol) in THF (100 mL) was added tetrabutylammonium fluoride trihydrate (1.84 g, 5.83 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between saturated aqueous NH4Cl solution and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3% MeOH in EtOAc) to give tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.01 g, 88%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](N1CCCC(N)C1)(OC(C)(C)C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:31][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-BOC-3-aminopiperidine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 442 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.27 (1H, br. s.) 8.02 (1H, d, J=5.47 Hz) 7.87 (1H, d, J=8.20 Hz) 7.80 (1H, d, J=5.37 Hz) 7.47 (1H, d, J=5.47 Hz) 7.31 (1H, dd, J=3.32, 2.54 Hz) 6.80 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.42, 1.76 Hz) 3.79 (3H, dd, J=6.78, 3.17 Hz) 2.76 (1H, t, J=12.45 Hz) 1.83 (1H, dd, J=12.93, 3.27 Hz) 1.65 (1H, dd, J=8.69, 3.22 Hz) 1.52 (1H, dd, J=11.76, 3.95 Hz) 1.37 (9H, s)
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(N=C=O)C=CC=CC=1.[N+:22]([CH2:25][CH3:26])([O-])=[O:23].C(O)C>O1CCCC1.C(N(CC)CC)C>[CH3:26][C:25]1[CH:4]2[CH:5]3[CH2:1][CH:2]([CH:3]2[O:23][N:22]=1)[CH:7]1[C:8](=[O:9])[O:10][C:11](=[O:12])[CH:6]31
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Reactant: CC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=NOC2C3CC(C12)C1C(=O)OC(=O)C31
Reaction time: 1 h

Procedure:
A solution of 4.0 g (24.4 mmol) of cis-5-norbornene-endo-2,3-dicarboxylic anhydride and 5.8 g (48.8 g) of phenyl isocyanate in 20 ml of tetrahydrofuran is treated dropwise with a solution of 1.83 g (1.76 ml, 24.4 mmol) of nitroethane and 6 drops of triethylamine in 10 ml of tetrahydrofuran. The mixture is maintained with stirring for 1 hour. The reaction mixture is filtered and the filtrate evaporated. Trituration with ethyl ether, filtration and drying gives 3.97 g of crude product. Trituration with 100 ml of ethanol (2 times) gives after filtration and drying 2.28 g of the title compound: m.p. 194°-197° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][CH3:19])[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-])=O.CO.[H][H]>[Pd].C(OCC)(=O)C>[CH2:17]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([NH2:1])[CH:5]=2)[CH2:18][CH3:19]
Reactant: CCCn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCn1c2c(c3cc(N)ccc31)CCCC2
Yield: 95.8 %

Procedure:
A solution of the compound obtained in Step 1 (270 mg, 1.05 mmol) and 10% palladium on carbon (50% wet, 10 mg, 0.09 mmol) in a mixed solvent of methanol (4 mL) and ethyl acetate (4 mL) was stirred at room temperature for 14 hr under 1 atm of hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 9-propyl-2,3,4,9-tetrahydro-1H-carbazol-6-amine (230 mg, 1.006 mmol, 96%) as a brown oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[CH3:16][C:17]1[O:21][C:20]([C:22]([F:25])([F:24])[F:23])=[C:19]([S:26](Cl)(=[O:28])=[O:27])[CH:18]=1>N1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][S:26]([C:19]1[CH:18]=[C:17]([CH3:16])[O:21][C:20]=1[C:22]([F:25])([F:23])[F:24])(=[O:28])=[O:27]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Reactant: Nc1cccc2cc(C3=NCCS3)[nH]c12
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cccc3cc(C4=NCCS4)[nH]c23)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a mixture of 2-(4,5-dihydro-1,3-thiazol-2-yl)-1H-indole-7-amine (100 mg) and pyridine (3 mL) was added 5-methyl-2-trifluoromethylfuran-3-sulfonyl chloride (150 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (90 mg, yield 46%) as pale-yellow crystals. M+1=430.