Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:43][C:42]2[CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=3)[CH:46]=[CH:47][C:41]=2[N:40]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.O>CN(C=O)C.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.[Cu]I>[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:43][C:42]2[CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:22]#[C:21][C:18]4[NH:17][C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=4)=[CH:50][CH:49]=3)[CH:46]=[CH:47][C:41]=2[N:40]=1)=[O:33])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc(-c3ccc(Br)cc3)cc2[nH]1)C(C)C
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(-c3ccc4nc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]c4c3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (62 mg, 0.195 mmol), (1-{2-[6-(4-Bromo-phenyl)-1-H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (73 mg, 0.146 mmol), Pd(PPh3)4 (11 mg, 0.00975 mmol), CuI (4 mg, 0.0195 mmol) and triethylamine (0.271 mL, 1.95 mmol) were suspended in DMF (2 mL). The reaction mixture was stirred at 80° C. for 3 hours then 1 mL of water was added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (12 mg, 11%). 1H NMR (MeOH-d4, 400 MHz) 7.66-7.64 (m, 2H), 7.59-7.50 (m, 4H), 7.24 (s, 1H), 6.98 (m, 1H), 5.28 (m, 1H), 5.12 (m, 1H), 4.28-4.19 (m, 2H), 4.04-3.82 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 2.43-2.01 (m, 10H), 0.99-0.87 (m, 12H); MS (ESI) m/z 737 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].Br[CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=C(OC)C(C)Br
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of 4-(2-nitro-4-trifluoromethylphenoxy) phenol (9.36 mm)., ethyl 4-bromo-3-methoxy-2-pentenoate (12 mm.) and K2CO3 (14 mm.) in acetone (20 ml.) is refluxed for 24 hours. After filtration, the filtrate is concentrated and the oily residue chromatographed on silica gel to yield ethyl 4-[4-(2-nitro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].Cl[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[C:13]1([CH2:12][CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCc1ccccc1
Reactant: c1c[nH]nn1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCC(C)(C)O
Product: c1ccc(CCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
1,2,3-Triazole (1634 mg, 23.7 mmol), sodium iodide (2364 mg, 15.8 mmol), sodium hydroxide (946 mg, 23.7 mmol) were added to t-amyl alcohol (6.2 ml), and the mixture was refluxed under stirring for 1 hour. 1-Chloro-2-phenylethane (2217 mg, 15.8 mmol) was dissolved in t-amyl alcohol (6.2 ml) and added dropwise under reflux over 1 hour. The mixture was refluxed under stirring for 3.5 hours. The mixture was cooled to room temperature and toluene (50 ml) was added. The mixture was washed with water (50×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/3) to give 1-(2-phenylethyl)-1H-1,2,3-triazole as a colorless oil (2.0 g, yield 73%). 2-(2-Phenylethyl)-2H-1,2,3-triazole (315 mg) was obtained as a colorless oil (yield 12%). 1-(4-phenylethyl)-1H-1,2,3-triazole
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)cc1
Yield: 14 %

Procedure:
Using 1.00 g of (4-chlorobenzyl)malononitrile, 10 ml of N,N-dimethylformamide, 1.0 g of sodium hydride (60% in oil), and :0.93 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.21 g of 2-(4-chlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (15)).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[C:10]2\[CH2:11][CH2:12][C:13]3[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][C:14]\2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:14]3[NH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc2c([nH]1)/C(=C/CCc1ccccc1)CC2
Agent: [Pd]
Product: CCOC(=O)c1cc2c([nH]1)C(CCCc1ccccc1)CC2

Procedure:
The title compound was synthesized from ethyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.55 mmol, 1 equiv) and 3-phenyl-propyl magnesium bromide (12.4 mL, 0.5M in THF, 6.2 mmol, 4 equiv) according to General Procedure 3 to give the exo olefin-containing compound (E)-ethyl 6-(3-phenylpropylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6 with 5% Pd on carbon, and was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 60% methanol and increasing to 100% over 7 minutes) afforded the title compound (42.1 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.67 (br. s., 1H), 7.28-7.33 (m, 2H), 7.16-7.23 (m, 3H), 6.64 (d, J=1.64 Hz, 1H), 4.25-4.34 (m, 2H), 3.00-3.09 (m, 1H), 2.51-2.68 (m, 5H), 1.97-2.07 (m, 1H), 1.65-1.77 (m, 3H), 1.47-1.55 (m, 1H), 1.34 (t, J=7.13 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])O.[Na+].Br[CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][Br:24])[C:17](Br)=[O:18]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(Cl)(Cl)Cl>[Br:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:16]1[C:17](=[O:18])[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[S:9]1
Reactant: CNc1ccccc1S
Reactant: O=C(Br)C(Br)CCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C(CCCCBr)Sc2ccccc21
Temperature: 5 °C

Procedure:
4.5 g (=0.032 m) of 2-(methylamino)-thiophenol, 6 g of triethylbenzylammonium chloride, and 11.20 g of sodium hydrogen carbonate were added to 120 ml of chloroform. The resulting suspension was cooled to 5° C., and then a solution of 10.88 g of 2,6-dibromohexanoyl bromide in 20 ml of chloroform was added dropwise so slowly that the temperature did not exceed 5° C. 20 minutes were required for the addition. The reaction mixture was then allowed to warm to room temperature and was subsequently heated under reflux for 4 hours. The reaction mixture was worked up by cooling and filtering it. The chloroform phase was washed, dried over sodium sulfate, and the solvent was distilled off. The 2-(4-bromobutyl)-4-methyl-2H-1,4-benzothiazine-3(4H)-one which formed was isolated from the remaining residue by fractional column chromatography. 2.78 g of white crystals having a melting point of 116° C. were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[N:22]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:22])=[O:21])=[CH:15]2)(=[O:7])=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.50 g), 1H-1,2,3-benzotriazol-1-ol (0.75 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.10 g) at room temperature. The mixture was stirred for 10 min, and 28% aqueous ammonia (1.70 mL) was added. The reaction mixture was stirred at room temperature for 3 hr, and water was added. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (1.46 g, yield 98%) as yellow crystals. melting point>300° C. (decomposition).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:29]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:28])[CH:22]=3)[C:13]=12>N1C=CC=CC=1>[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:29]3[CH2:30][CH2:31][C:32](=[O:35])[CH2:33][CH2:34]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:8]([NH:7][C:3]4[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=4)=[O:9])=[C:23]([F:28])[CH:22]=3)[C:13]=12
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)cc1F
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCC(=O)CC4)c4ncnc(N)c34)cc2F)c1
Reaction time: 16 h
Yield: 81.4 %

Procedure:
m-Tolyl isocyanate (1.2 equiv., 37.7 mg, 0.283 mmol) was added to a solution of 4-[4-amino-3-(4-amino-3-fluorophenyl) 1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (80.3 mg, 0.236 mmol) in pyridine. After 16 h at 40° C., the reaction was quenched with water (2 mL) and evaporated to dryness. Purification by preparative RP-HPLC (10% to 40% CH3CN in 0.1 N aqueous ammonium acetate, buffered to pH 4.5, over 60 min at 10 mL/min using a Waters Deltapak C18, 15 μm, 100×40 mm column, λ=254 mm) gave N-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea (91 mg, 84%); 1H NMR (DMSO-d6, 400 MHz) δ 2.26 (2H, br t), 2.30 (3H, s), 2.43 (4H, m), 2.69 (2H, m), 5.26 (1H, m), 6.82 (1H, d), 7.18 (1H, t), 7.25 (1H, br d), 7.32 (1H, br s), 7.45 (2H, m), 8.26 (1H, s), 8.36 (1H, t), 8.72 (1H, d) and 9.05 (1H, s) and RP-HPLC (10 to 90% CH3CN in 0.1 N aqueous ammonium acetate, buffered to pH 4.5, over 12 min at 2 mL/min using a Waters Symmetry C18, 5 μm, 250×4.6 mm column) Rt=15.433 min, 97.9%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=C(C=CC=1)C(OO)=[O:21].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:4]=1[OH:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(OC(F)(F)F)ccc1C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethoxy)benzaldehyde (1.0 g, 4.542 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (2.04 g, 9.08 mmol). The resulting clear solution was stirred for 16 hours at room temperature. A white precipitate had formed and this was filtered off. The filtrate was evaporated to a white solid, which was diluted with ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulphate, and evaporated to a white solid. This solid was redissolved in methanol (15 mL), and treated with triethylamine (2 mL, 10 mmol). After stirring for two hours, the solvents were evaporated. The residue was taken up in ethyl acetate (25 mL), and washed with 1N citric acid solution (20 mL) and brine (20 mL) dried over sodium sulphate, and evaporated to an oil. This crude material was then purified by eluting through a short pad of silica with dichloromethane, which afforded the title compound as a clear oil (650 mg, 57%)
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[C:12]([C:27]([O:29][CH3:30])=[O:28])=[N:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][NH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41](=O)[O:42]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C>[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][C:41]([N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([C:14]3[N:13]=[C:12]([C:27]([O:29][CH3:30])=[O:28])[C:11]([O:10][CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:16][CH:15]=3)[CH:26]=2)[CH2:21][CH2:22][CH2:23]1)=[O:42]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OCCOc1ccccc1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1OCCOc1ccccc1
Yield: 98.2 %

Procedure:
Methyl 3-(2-phenoxyethoxy)-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (27C) (81 mg, 0.2 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (127 mg, 0.4 mmol) were heated to reflux in acetonitrile (5 mL) for 24 hours. After cooling, the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of PE (100%) to PE/EtOAc (4:6), to provide 114 mg (97%) of the desired product methyl 641-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinate (27D). 1H NMR (300 MHz, CDCl3) δ8.12 (1H, s), 7.85 (1H, d), 7.73 (1H, m), 7.44 (3H, m), 7.29 (4H, m), 7.09 (1H, m), 6.94 (3H, m), 4.44 (2H, m), 4.37 (2H, m), 3.88 (2H, m), 3.78 (3H, m), 2.74 (2H, m), 2.00 (2H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:15])([F:14])[C:7]1[CH:8]=[C:9]([CH2:12]O)[S:10][CH:11]=1>>[Cl:3][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:6]([F:15])([F:14])[F:5])[CH:8]=1
Reactant: OCc1cc(C(F)(F)F)cs1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1csc(CCl)c1
Reaction time: 3 h
Yield: 49.9 %

Procedure:
Thionyl chloride (4.89 g) was added to [4-(trifluoromethyl)thiophen-2-yl]methanol (500 mg) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (275 mg).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:12]=1)=[O:10])C.[OH-].[Na+]>CO>[OH:28][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:18]=[CH:17]/[C:13]1[N:12]=[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[O:10])[CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(C(=O)NCCCC(=O)OCC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)NCCCC(=O)O)n1
Yield: 62.7 %

Procedure:
Under the conditions of example 2, 60 mg of 4-{6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridylcarbonylamino}-butyric acid ethyl ester in 1.5 ml of methanol is saponified with 1.5 ml of 1 n sodium hydroxide solution and worked up. 35 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([N:20]([CH:34]1[CH2:36][CH2:35]1)[C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[C:6]([C:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=1)=O)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:45]>>[CH2:1]([O:3][C:4]([C:5]1[N:20]([CH:34]2[CH2:35][CH2:36]2)[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=2)=[N:45][C:6]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=1)=[O:37])[CH3:2]
Reactant: CCOC(=O)C(C(=O)c1ncn(Cc2ccccc2)n1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1c(-c2ncn(Cc3ccccc3)n2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1

Procedure:
The title compound was prepared from 3-(1-benzyl-1H-[1,2,4]triazol-3-yl)-2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-propionic acid ethyl ester in direct analogy to intermediate 8B, by reaction with ammonium trifluoroacetate. MS: 498.2 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35](C3CCCCO3)[N:34]=[CH:33][CH:32]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[C:42]12([NH:48]C(=O)OC(C)(C)C)[CH2:47][CH:46]1[CH2:45][NH:44][CH2:43]2.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.CCOC(C)=O.C(Cl)Cl>[NH2:48][C:42]12[CH2:47][CH:46]1[CH2:45][N:44]([C:11]1[C:30]([C:31]3[NH:35][N:34]=[CH:33][CH:32]=3)=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)=[O:16])=[CH:13][N:12]=1)[CH2:43]2
Reactant: CC(C)(C)OC(=O)NC12CNCC1C2
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC12CC1CN(c1ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc1-c1ccn[nH]1)C2
Temperature: 140 °C
Reaction time: 18 h

Procedure:
DIPEA (96 μL, 0.55 mmol) was added to a mixture of 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1, 117 mg, 0.25 mmol) and (tert-butyl 3-azabicyclo[3.1.0]hexan-1-ylcarbamate, 59.2 mg, 1.2 mmol) in iPrOH (250 μL) in a vial, which was sealed and the RM mixture was stirred at 140° C. for 18 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in DCM (1 mL), cooled to 0° C., treated with TFA (0.45 mL, 5.85 mmol) and was stirred at RT for 3 h. The RM was poured into 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 2-EP, from 22% to 27% in 6 min) to afford the title compound as an amorphous white powder. HPLC (Condition 4) tR=4.2 min, UPLC-MS (Condition 3) tR=0.76 min, m/z=445.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.56-0.71 (m, 1H) 0.96-1.10 (m, 1H) 1.61-1.79 (m, 1H) 2.26 (s, 1H) 3.22-3.37 (m, 1H) 3.44 (d, J=1.00 Hz, 1H) 3.70 (d, J=1.00 Hz, 1H) 6.40 (d, J=1.56 Hz, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.84 (d, J=8.99 Hz, 3H) 8.07 (d, J=2.35 Hz, 1H) 8.71 (br. s, 1H) 10.24 (s, 1H) 13.00 (br. s, 1H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](/[C:24](/[CH3:31])=[CH:25]/[C:26](OCC)=[O:27])=[CH:20][CH:19]=1.Cl>C1COCC1.CO>[Br:17][C:18]1[CH:19]=[CH:20][C:21](/[C:24](/[CH3:31])=[CH:25]/[CH2:26][OH:27])=[CH:22][CH:23]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: C/C(=C\CO)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A 1M solution of DIBAL-H in toluene (42 ml, 42 mmol) was added dropwise, at −70° C. over 30 min, to a stirred solution of (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (4.55 g, 16.92 mmol) in dry THF (100 ml), and the mixture stirred for 1 h. Methanol (5 ml) was carefully added, followed by 1N HCl (300 ml) and the resulting mixture extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine, dried (Na2SO4), and evaporated to give the crude product as an off-white solid, which was purified by recrystallisation from hot 1:4 ether/n-heptane (250 ml) to give the product (E)-3-(4-bromophenyl)-but-2-en-1-ol as colourless needles: 3.10 g (81%)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH:20]=[CH:21][C:22]2[C:30]3[C:25](=[CH:26][C:27]([NH:31][C:32]4[N:40]=[CH:39][CH:38]=[CH:37][C:33]=4[C:34](O)=[O:35])=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:14]=1.[CH:41]1([C:44]#[C:45][CH2:46][NH2:47])[CH2:43][CH2:42]1>>[CH:41]1([C:44]#[C:45][CH2:46][NH:47][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[N:40][C:32]=2[NH:31][C:27]2[CH:26]=[C:25]3[C:30]([C:22](/[CH:21]=[CH:20]/[C:15]4[CH:14]=[C:13]([CH3:12])[CH:18]=[C:17]([CH3:19])[N:16]=4)=[N:23][NH:24]3)=[CH:29][CH:28]=2)[CH2:43][CH2:42]1
Reactant: NCC#CC1CC1
Reactant: Cc1cc(C)nc(C=Cc2n[nH]c3cc(Nc4ncccc4C(=O)O)ccc23)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C)nc(/C=C/c2n[nH]c3cc(Nc4ncccc4C(=O)NCC#CC4CC4)ccc23)c1

Procedure:
Prepared-in a similar manner to that described for Example 6 above, except using 2-{3-[2-(4,6-Dimethyl-pyridin-2-yl)-vinyl]-1H-indazol-6-ylamino}-nicotinic acid p-toluene sulfonate and 3-Cyclopropyl-prop-2-ynylamine. 1H NMR (DMSO-d6): δ 13.01 (1H, s), 11.20 (1H, s), 9.19 (1H, bt), 8.51 (1H, s), 8.40 (1H, d, J=4.9 Hz), 8.15 (1H, d, J=7.5 Hz), 8.05 (1H, d, J=8.7 Hz), 7.83 (1H, d, J=16.4 Hz), 7.42 (1H, d, J=16.4 Hz), 7.31 (1H, s), 7.05 (1H, d, J=8.3 Hz), 6.96 (1H, s), 6.92 (1H, dd, J=7.5, 4.9 Hz), 4.06 (2H, d, J=4.14 Hz), 2.46 (3H, s), 2.29 (3H, s), 1.33–1.28 (1H, m), 0.77–0.72 (2H, m), 0.60–0.55 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(OCC)(=O)C.O>[Cl:16][CH2:17][CH2:18][C:19]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1NC(=O)CCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of 2,6-dimethylaniline (60.5 g) and potassium carbonate (45 g) is dissolved in a 3:1 mixture of ethyl acetate and water (1,200 ml). To the ice-cooled mixture, 100 ml of an ethyl acetate solution of 3-chloropropionyl chloride (52.5 ml) is added dropwise under agitation. The reaction mixture is stirred for 3 hours at room temperature and the aqueous layer is subsequently separated. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and subsequently dried over Glauber's salt. Upon distilling off the solvent under vacuum, a colorless powder results. Recrystallization from ethanol provides a colorless needle in an amount of 96.5 g (yield: 90.8%). m.p. 131° C.