Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:24])=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:33][CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:24])=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)NC3=O)cc12
Agent: Cl
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N(CCN4CCCC4)C3=O)cc12

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 36) and 1-(2-chloroethyl)pyrrolidine hydrochloride following General Procedure H.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:23]([NH:24][C:25]([O:27]C(C)(C)C)=O)=[CH:22][N:21]=[C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:19]=1)C(OC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:27]=[C:25]1[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[C:23](=[CH:22][N:21]=[C:20]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:19]=2)[NH:24]1
Reactant: COC(=O)C(Cc1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1Cc2cc(-c3ccccc3)ncc2NC1=O)OCc1ccccc1
Yield: 64.9 %

Procedure:
A solution of 3E (980 mg, 1.94 mmol) in TFA (2 mL) and CH2Cl2 (2 mL) was stirred at RT for 2 h. After this time, no starting material was detected by LC-MS. The reaction was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (30-100%) in hexane to give the title compound as a white solid (470 mg, 65%). LC/MS (method A): retention time=2.72 min, (M+H)+=374.
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH2:18]([N:20](CC)CC)C.CN.CO>C(Cl)(Cl)Cl>[CH3:18][NH:20][CH2:6][CH2:7][S:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)OCCSc1cccc2nccn12
Agent: CN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNCCSc1cccc2nccn12
Yield: 47.1 %

Procedure:
A solution of 5-[2-(methylsulfonyloxy)ethylthio]imidazo[1,2-a]pyridine (2.18 g, 8 mmoles), triethylamine (2.24 ml, 16 mmoles) and a 40% methylamine-methanol solution (20 ml) in chloroform (20 ml) was heated at reflux for 3 hours. The reaction solution was washed with an aqueous 3N-sodium hydroxide solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: methanol/chloroform=1:10) to obtain 781 mg of the desired product (47.1%, light brown oily product).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.S(Cl)(Cl)=O.[Al+3].[Cl-:19].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:19][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[N:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: Cn1nnc2ccc(C(=O)O)cc21
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cn1nnc2ccc(C(=O)c3ccc(Cl)cc3)cc21

Procedure:
The carboxylic acid (b) is converted into the corresponding acid chloride with thionyl chloride and then reacted with chlorobenzene and AlCl3, yielding the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23]>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([OH:23])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Brc1ccc2ccccc2c1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccc2ccccc2c1
Yield: 91.6 %

Procedure:
With 11.1 g of 2-bromonaphthalene and 5.00 g of 5-chloroisatin as starting materials, 7.81 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:32]=[CH:31][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27](OC)=[O:28])=[O:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].Cl.[NH2:41][OH:42]>CO.C[O-].[Na+]>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:32]=[CH:31][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([NH:41][OH:42])=[O:28])=[O:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1C[C@]2(CCCO2)C[C@H]1NC(=O)c1ccc(C2CCOc3ccccc32)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2CCOc3ccccc32)cc1
Reaction time: 1 h
Yield: 34 %

Procedure:
Methyl (5R,7S,8R)-8-{[4-(3,4-dihydro-2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction 34f (0.095 g, 0.22 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.032 g, 34%) as a white solid. MS found: (M+H)+=435.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([O:19][P:20]([CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1)([O:21][CH2:22][CH3:23])=[O:24])[CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Product: CCOP(=O)(Cc1cnc(NC(=O)OC(C)(C)C)cn1)OCC
Temperature: 140 °C
Yield: 59.8 %

Procedure:
tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (2.5 g, 8.71 mmol) and triethylphosphite (1.8 ml, 10.45 mmol) were placed in a 25 mL round bottom flask. A distillation apparatus was attached to collect the poisonous ethyl bromide formed during the reaction. The reaction mixture was heated to 140° C. for 30 minutes and then cooled to room temperature. The reaction mixture was purified by flash column chromatography (10% to 30% Ethyl acetate/Hexane) to afford title product (1.8 g, 60% yield). 1H NMR (600 MHz, CDCl3) δ 9.19 (s, 1H), 8.22 (t, J=1.8 Hz, 1H), 7.37 (s, 1H), 4.12-4.07 (m, 4H), 3.38 (s, 1H), 3.34 (s, 1H), 1.54 (s, 9H), 1.29 (t, J=7.2 Hz, 6H). MS m/z: 346 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28]([N:15]1[CH:16]2[CH:21]([CH:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][CH2:17]2)[N:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)=[O:29]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (100.9 mg, 0.25 mmol) was dissolved in absolute CH2Cl2 (13 ml) under a nitrogen atmosphere and methyl chloroformate (28.9 mg, 0.31 mmol) was added dropwise. The solution was stirred at room temperature for 2 hours. Thereafter, the mixture was evaporated in vacuo and the residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=16 cm, V=5 ml) and was obtained as a yellow resin.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]2[C:13](=[O:14])[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)[CH:7]=1.[Cu][C:22]#[N:23].C(Cl)Cl.[OH-].[NH4+]>CN(C=O)C>[CH3:20][O:19][C:5]1[CH:4]=[CH:3][C:2]([C:22]#[N:23])=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1
Reactant: COc1ccc(Br)cc1C1Oc2ccccc2NC1=O
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C#N)cc1C1Oc2ccccc2NC1=O
Temperature: 160 °C
Yield: 88.5 %

Procedure:
To a solution of 2-(5-bromo-2-methoxyphenyl)-2H-1,4-benzoxazin-3(4H)-one (I11) (0.90 g, 2.70 mmoles) in DMF (10 mL) was added copper (I) cyanide (1.3 g, 5 equiv.) and the mixture heated at 160° C. for 12 hours. The mixture was cooled and methylene chloride (100 mL) and aqueous ammonium hydroxide (10 mL) were added. The methylene chloride layer was separated and dried over MgSO4 which afforded the required product (I12) (0.67 g, 89%) upon evaporation in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][S:15]([CH3:17])=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.[CH2:46]([NH2:54])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>ClCCl>[CH3:17][S:15]([CH2:14][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:54][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:12])=[O:16]
Reactant: CS(=O)CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)C(CCS(C)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a mixture of 2-((tert-butoxycarbonyl)amino)-4-(methylsulfinyl)butanoic acid (10.0 g, 37.7 mmol) and HOBt (6.35 g, 41.5 mmol) in dichloromethane (200 mL) at 0° C. was added triethylamine (10.5 mL, 75.4 mmol) and EDAC (7.95 g, 41.5 mmol). After stirring for 20 minutes octylamine was added and the solution was allowed to warm to room temperature and stirred for 3 days. The reaction was washed with saturated sodium bicarbonate (2×100 mL), 1N HCl (2×100 mL), and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil which solidified upon standing. The solid was purified by silica gel chromatography with 0-5% methanol/dichloromethane to give a white solid (13.1 g, 92%). m/z 377 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[H-].[Na+]>CS(C)=O>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccc(C)nc1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccc(C)nc2)C1
Yield: 3 %

Procedure:
Preparation of the title compound was carried out according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 2-methyl-5-vinylpyridine (1 mL, 2.3 mmol) and NaH (120 mg, 3 mmol) in DMSO (4 ml) at 120° C. for 48 h to obtain 10 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=399.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH:10]([C:14]2[N:15]=[CH:16][N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH:25]1([O:31][C:32]([O:34][CH:35](Cl)[CH3:36])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH:10]([C:14]2[N:15]=[CH:16][N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)[C:11]([O:13][CH:35]([O:34][C:32]([O:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])[CH3:36])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(OC(=O)OC1CCCCC1)OC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Yield: 41.3 %

Procedure:
A solution of 50.0 mg (0.16 mmol) of the compound from example 1i and 39 mg (0.19 mmol) of 1-cyclohexyloxycarbonyloxy-1-ethyl chloride, 13 mg (0.08 mmol) of KI and 26 mg (0.19 mmol) of K2CO3 in 2 ml of DMF was stirred at 60° C. for 12 h. Then 5 ml of water were added and the reaction solution was extracted several times with EA. The combined EA extracts were dried, filtered and concentrated to dryness. The resulting residue was purified on silica gel with CH2Cl2/methanol as mobile phase, resulting in 32 mg of the title compound in the form of an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]#C)[C:3]=1[CH2:12][CH2:13][CH3:14].[F-].[Cs+].[CH2:17](OCC)C>CCN(C1C=CC=CC=1)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:17]=[C:9]([CH3:10])[O:8][C:4]=2[C:3]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCOCC
Reactant: C#CCOc1cccc(F)c1CCC
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(F)ccc2cc(C)oc12
Yield: 40 %

Procedure:
A suspension of 1.5 g (7.8 mmol) of 1-fluoro-2-propyl-3-prop-2-ynyloxy-benzene and 1.7 g (11.15 mmol) of caesium fluoride in 14 ml of diethylaniline was heated at reflux in a metal bath for 4 hours. After cooling to room temperature 100 ml of diethyl ether were added thereto and insoluble constituents were filtered off. The diethyl ether phase was washed three times with 60 ml of 1 N hydrochloric acid, dried over sodium sulfate and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:2). There was obtained 0.6 g (40%) of 6-fluoro-2-methyl-7-propyl-benzofuran as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2cc(Cl)ncn2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccncn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an argon purged solution of cis/trans-4-(6-chloro-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (1.05 g, 3.69 mmol) and triethylamine (0.52 ml, 3.69 mmol) in ethyl acetate (37 ml) was added palladium on charcoal 10% (0.078 g). The reaction mixture was purged with hydrogen gas and stirred under an atmosphere of hydrogen gas for 16 h at room temperature. The catalyst and the ammonium salts were removed by filtration over Decalite. The filtrate was concentrated in vacuo to give the title compound (0.92 g) as light yellow oil in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2([CH2:35]Cl)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[CH3:44][NH2:45]>ClCCl>[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2([CH2:35][NH:45][CH3:44])[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)C2(CCl)C=CC=CN2)c1
Reactant: CN
Solvent: ClCCl
Product: CNCC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
Into a 10-mL vial, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(2-(chloromethyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (150 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (5 mL), methylamine (2 mL). The resulting solution was stirred for 48 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10-1:5). The product was obtained as 110 mg (74%) of a yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:5][CH:4]=1.[N:21]#[C:22][NH2:23].CC(C)([O-])C.[K+].BrN1C(=O)CCC1=O>CO>[C:22]([N:23]=[S:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:19][CH:20]=1)[CH3:1])#[N:21]
Reactant: N#CN
Reactant: CSc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: CC(C)(C)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CO
Product: CS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 1 h

Procedure:
A solution of 2-(4-(methylthio)benzyl)isoindoline-1,3-dione (preparation 6a, 3.60 g, 12.71 mmol), cyanamide (694 mg, 16.5 mmol) and potassium tert-butoxide (1.71 g, 15.25 mmol) in methanol (30 mL) is treated with N-bromosuccinimide (3.39 g, 19.06 mmol). The mixture is stirred for 1 h and concentrated under reduced pressure. Saturated aqueous Na2S2O3 solution is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate to ethyl acetate/methanol 4:1). Yield: 2.43 g (59% of theory); ESI mass spectrum: [M+H]+=324; r.t. HPLC: 0.52 min (X001_004).
Reaction SMILES: I[C:2]1[C:3]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][CH:6]=1.I[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17]>[Cu].CN(C=O)C>[F:12][C:7]([F:13])([C:3]1[C:2]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[CH:6][NH:5][N:4]=1)[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)C(F)(F)c1n[nH]cc1I
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)c1c[nH]nc1C(F)(F)C(F)(F)F
Temperature: 122.5 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
4-Iodo-3-pentafluoroethyl-1H-pyrazole (12.48 g), copper powder (7.63 g), iodopentafluoroethane (29.50 g) and DMF (60 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 120-125° C. After cooling to room temperature, the insoluble material was filtered off through Celite and washed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The organic phase was washed with water and dried over sodium sulfate, and concentrated under the reduced pressure. The crude product was distilled under reduced pressure to obtain 3,4-bis-pentafluoroethyl-1H-pyrazole (1.20 g), bp. 110-115° C./20 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]1[NH:52][CH2:51][CH2:50][N:49]2[CH2:53][CH2:54][CH2:55][C@H:48]12.CN(C)C(=O)C>CC1CCCO1>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([C:4]([N:52]2[CH2:51][CH2:50][N:49]3[CH2:53][CH2:54][CH2:55][C@@H:48]3[CH2:47]2)=[O:6])=[CH:7][C:8]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])(=[O:14])=[O:13]
Reactant: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl)N1CCN2CCC[C@@H]2C1
Reaction time: 0.75 h

Procedure:
To 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.197 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (919 mg, 2.416 mmol) in 2-methyltetrahydrofuran (15 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (388 mg, 3.08 mmol). The reaction was stirred at room temperature for 45 minutes at which time N,N-dimethylacetamide (1 mL) was added. The reaction was stirred for an additional 45 minutes and N,N-dimethylacetamide (3 mL) was added. The reaction was stirred for an addition 2.5 hours, diluted with 2-methyltetrahydrofuran (15 mL), and washed with a solution of 6% sodium bicarbonate and 6% brine (2×15 mL). The aqueous layers were combined and re-extracted with 2-methyltetrahydrofuran (15 mL). The organic layer was washed with saturated brine (4×25 mL), dried over MgSO4, and concentrated. The residue was taken up in ethanol (20 mL) and reconcentrated to give the title compound.
Reaction SMILES: FC1C=CC([NH:8][C:9]([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)=[O:10])=CC=1.C([N:19](CC)CC)C>C1COCC1>[C:11]1([C:14]([NH2:19])=[O:15])([C:9]([NH2:8])=[O:10])[CH2:13][CH2:12]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: NC(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl chloride prepared via the procedure in Example 47 (0.13 g, 0.538 mmol), Example A9 (0.123 g, 0.414 mmol), and triethylamine (0.065 ml, 0.621 mmol) were dissolved in THF (3 ml). The mixture was stirred at RT for 30 min, filtered to remove triethylamine HCl, concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM) to obtain N-(2-fluoro-5-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.067 g, 32% yield). MS (ESI) m/z: 504.2 (M+H+).