Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[CH2:40]([S:48](Cl)(=[O:50])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][N:37]([S:48]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:50])=[O:49])[CH2:36][CH2:35]1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: O=S(=O)(Cl)CCc1ccccc1
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(S(=O)(=O)CCc3ccccc3)CC2)cc1F
Yield: 101.3 %

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (228 mg) and phenethylsulfonyl chloride (409 mg), respectively, to provide crude 4-(2,5-difluoro-4-methoxyphenyl)-1-phenethylsulfonylpiperazine (401 mg).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH:6]([CH3:28])[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=O>C1COCC1>[CH3:28][CH:6]([CH2:7]/[CH:8]=[CH:39]\[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][Br:29])[CH2:5][C:2]([OH:4])=[O:3]
Reactant: CC(CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)O
Reactant: O=CCCCCCCCCCBr
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C/C=C\CCCCCCCCCBr)CC(=O)O
Yield: 58.4 %

Procedure:
68.1 g (149 mmol) of (4-carboxy-3-methyl-butyl)-triphenylphosphonium bromide were placed in 150 ml of THF and treated with 33.4 g (298 mmol) of potassium t-butylate in 50 ml of THF. 35 g (149 mmol) of 10-bromodecanal were added to this mixture After usual work up 111.8 g of crude product were obtained and, after chromatography, 29 g of 3-methyl-5Z-15-bromopentadec-5-enoic acid were obtained having the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:9])[C:5](I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:18]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:28][C:27]([C:5]2[C:6]([CH2:8][Cl:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:29])[CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: ClCc1nc(Cl)ccc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(Cl)nc2CCl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-chloro-2-chloromethyl-3-iodo-pyridine (2.5 g, 8.7 mmol, 1 eq) in dry THF (25 mL) was added i-PrMgCl.LiCl complex (1.3M in THF, 7.37 mL, 9.6 mmol, 1.1 eq) at −20° C. in drop wise manner over period of 10 minutes. Pre-dissolved solution of N-boc-3-azetidinone (1.78 g, 10.4 mmol, 1.2 eq) in dry THF (10 mL) was added at −20° C. to above reaction mixture. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After maximum consumption of starting material, reaction mixture was cooled to 0° C., quenched with 10% citric acid solution (20 mL) and extracted with ethyl acetate (3×100 mL). Combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown oil (4.5 g, crude). Crude of title compound was used as such for next reaction. LC-MS (m/z): 332.9 (M+H).
Reaction SMILES: C[O-].[Na+:3].CO.[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH2:37][CH2:38][C:39]([F:51])([F:50])[C:40]([F:49])([F:48])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[C:34]([OH:36])=[O:35])[C:12]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)([CH3:17])[CH2:13][S:14]2)=[CH:9][CH:8]=1>C(OCC)C>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH2:37][CH2:38][C:39]([F:51])([F:50])[C:40]([F:48])([F:49])[C:41]([F:46])([F:47])[C:42]([F:43])([F:44])[F:45])[C:34]([O-:36])=[O:35])[C:12]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)([CH3:17])[CH2:13][S:14]2)=[CH:9][CH:8]=1.[Na+:3]
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium methoxide in methanol (1.0 mol/l, 0.145 ml, 0.145 mmol) was added to a methanol (1 ml) solution of the 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid prepared in Example 8 (100 mg, 0.145 mmol), followed by stirring for 2 hours at room temperature. After addition of ethyl ether, the reaction mixture was evaporated under reduced pressure to remove the solvent, thereby giving sodium 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[F:12][C:13]([F:35])([F:34])[C:14]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]2=[O:31])=[CH:22][CH:21]=1)([OH:19])[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:23]3[CH:32]=[CH:33][C:20]([C:14]([OH:19])([C:13]([F:12])([F:34])[F:35])[C:15]([F:18])([F:16])[F:17])=[CH:21][CH:22]=3)[C:26](=[O:31])[CH2:27]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: O=C1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C(=O)C2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a stirring solution of 4-amino-3-fluorobenzoic acid (1.965 mmol, 305 mg), 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-2-one (1.965 mmol, 700 mg) and triethylamine (5.89 mmol, 596 mg) in dichloromethane (10 mL) was added 1-propanephosphonic acid cyclic anhydride (2.95 mmol, 1876 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (30 mL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with 50% ethyl acetate/50% dichloromethane—100% ethyl acetate gradient) to afford the title compound (550 mg). MS (ESI) m/z 492.3 [M−H]−
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]OS(C)(=O)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][NH2:23]>>[CH:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8][NH:23][CH3:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCC1
Reactant: CN
Product: CNC[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Yield: 43 %

Procedure:
A mixture of crude tert-butyl (S)-3-cyclopentyl-1-(methanesulfonyloxy)propan-2-ylcarbamate in ethanolic methylamine (30 mL) was heated under reflux overnight. The solvent was removed in vacuo and the residue was purified by silica chromatography to obtain tert-butyl (S)-3-cyclopentyl-1-(methylamino)propan-2-ylcarbamate (900 mg, 43% for 3 steps from) as a solid (900 mg, yield 43% for 3 steps from tert-butyl (S)-3-cyclopentyl-1-(t-butyldimethyl-silyloxy)propan-2-ylcarbamate). 1H NMR (CDCl3, 400 MHZ) δ 1.10 (m, 2 H), 1.44 (s, 9 H), 1.49 (m, 3 H), 1.60 (m, 3 H), 1.81 (m, 3 H), 2.69 (s, 3H), 2.90 (m, 1 H), 3.17 (m, 1 H), 3.92 (brs, 1 H), 5.66 (brs, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25](Br)=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][C:38]([N:40]1[CH:45]([C:46]2[NH:50][C:49]3[CH:51]=[C:52](B4OC(C)(C)C(C)(C)O4)[CH:53]=[CH:54][C:48]=3[N:47]=2)[CH:44]2[CH2:64][CH:41]1[CH2:42][CH2:43]2)=[O:39])([CH3:36])([CH3:35])[CH3:34].C([O-])(O)=O.[Na+]>COCCOC.O>[C:33]([O:37][C:38]([N:40]1[CH:45]([C:46]2[NH:50][C:49]3[CH:51]=[C:52]([C:25]4[CH:26]=[CH:27][C:28]5[C:29]6[C:20](=[CH:19][C:18]([C:15]7[NH:14][C:13]([CH:9]8[CH2:10][CH2:11][CH2:12][N:8]8[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:17][CH:16]=7)=[CH:31][CH:30]=6)[CH2:21][CH2:22][C:23]=5[CH:24]=4)[CH:53]=[CH:54][C:48]=3[N:47]=2)[CH:44]2[CH2:64][CH:41]1[CH2:42][CH2:43]2)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(Br)ccc2-3)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 80 °C
Yield: 59 %

Procedure:
Pd(Ph3)4 (20 mg, 0.017 mmol) was added to a mixture 2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (173 mg, 0.35 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (154 mg, 0.35 mmol), NaHCO3 (103 mg, 1.22 mmol) in 1,2-dimethoxyethane (5 mL) and water (1 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 3-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a white solid (150 mg, 59%). m/z 727.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([CH3:26])=[CH:24][C:18]([CH:19]=[CH:20][C:21](O)=O)=[C:17]([CH3:27])[CH:16]=1>>[CH3:13][O:14][C:15]1[C:25]([CH3:26])=[CH:24][C:18](/[CH:19]=[CH:20]/[C:21]2[NH:1][C:2]3[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=3[N:8]=2)=[C:17]([CH3:27])[CH:16]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1cc(C)c(C=CC(=O)O)cc1C
Product: COc1cc(C)c(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)cc1C
Yield: 19.6 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 1.0 g (5.88 mmol) of 5,6-diamino-1,3-dimethyluracil and 1.33 g (6.45 mmol) of 4-methoxy-2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide to give 393 mg (yield 20%) of Compound 101 as pale yellow grains.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17](=[S:19])[NH2:18])=[C:4]2[CH2:3]1.[Cl:20][CH2:21][C:22](=O)[CH2:23]Cl>O1CCOCC1>[Cl:20][CH2:21][C:22]1[N:18]=[C:17]([C:16]2[N:15]=[CH:14][N:5]3[C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=4[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=23)[S:19][CH:23]=1
Reactant: CN1Cc2c(C(N)=S)ncn2-c2ccccc2C1=O
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccccc2C1=O
Yield: 49.6 %

Procedure:
A yellow suspension of 8.60 g (0.0316 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide in 200 ml of dioxan was treated with 4.41 g (0.0347 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 3 hrs., cooled and filtered. The solution was boiled at reflux for a further 16 hrs., cooled and suction filtered. The product was recrystallized from hot acetonitrile. There were obtained 5.4 g (65%) of 3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals. An analytical sample could be obtained from the mother liquor after chromatography (silica gel, cyclohexane/ethyl acetate 1:1) and recrystallization (acetonitrile); m.p. 248-249°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Br:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([CH3:16])[N:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example A.41) (0.4 g, 0.5 mmol) and commercially available 3-bromo-benzene-boronic acid (0.38 g, 1.89 mmol) according to the general procedure IVb. Obtained as an orange solid (0.23 g, 40%). MS (ISP) 394.9 [(M+H)+]; mp 132.5° C.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:13]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:12]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CN(C)C=O>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:5]2[N:10]=[CH:9][C:8]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[C:13]([C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[C:27](=[O:31])[CH2:26][CH2:25]5)[CH:12]=3)=[CH:7][N:6]=2)[CH2:35][CH2:34]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1ncc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cn1
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(-c3cc(-c4ccc5c(c4)CCC5=O)c(-c4ccncc4)o3)cn2)CC1
Temperature: 90 °C
Yield: 57 %

Procedure:
A solution of the product from Step 6 (0.15 g, 0.35 mmol) in dry dimethylformamide (2 ml) was treated with N-methylpiperazine (0.077 ml, 0.70 mmol) and heated at 90° C. for 2 hours. After cooling to room temperature the reaction mixture was applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and chromatographed on silica gel eluting with 0.880 ammonia/methanol/dichloromethane solution (0.5:4.5:95) to afford the title compound (0.09 g, 57%); MS(ES+) m/e 452 [M+H]+.
Reaction SMILES: C[O:2][C:3]1([CH3:10])O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C[Si](C)(C)[Cl:13]>C(Cl)Cl>[Cl:13][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[CH3:10]
Reactant: COC1(C)OC2CCC2O1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CC[C@H]1Cl
Yield: 88.8 %

Procedure:
14.4 g (0.1 mol) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 16.2 g (0.149 mol) of trimethylchlorosilane in 50 ml of methylene chloride are heated under reflux for 15 hours. Stripping off the solvent and fractional distillation of the residue gives 13.2 g (89%) of trans-1-chloro-2-acetoxy-cyclobutane. Boiling point10 66°, nD20 1.4472.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1F
Product: CC1(c2ccccc2)CCN(c2nccc(-c3ccc(F)cc3F)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 2,4-difluorophenylboronic acid. LC-MS Method 3, tR=1.238 min, m/z=785. 1H NMR (CDCl3) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.58-3.67 (m, 1H), 4.35-4.45 (m, 1H), 6.93-7.08 (m, 2H), 7.30-7.48 (m, 5H), 7.62-7.65 (m, 1H), 8.15-8.23 (m, 1H), 8.78-8.81 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[N:10]=[C:9]3[C:5]=2[N:6]([CH3:11])[CH:7]=[N:8]3)=[CH:14][CH:15]=1
Reactant: Cn1cnc2nc(Cl)nc(Nc3ccc(Cl)cc3)c21
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3c(ncn3C)n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-7-methyl-7H-purin-6-yl)-(4-chloro-phenyl)-amine and 3,5-dimethylpyrazole.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([SH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([S:19][C:2]2[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: FC(F)(F)c1nnc(Br)s1
Reactant: Sc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)c1nnc(Sc2ccc(Cl)c(Cl)c2)s1
Reaction time: 2 h
Yield: 67.3 %

Procedure:
130.5 g (0.66 mole) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole were added dropwise to a solution of 98.1 g (0.66 mole) of 3,4dichloro-thiophenol and 57.6 g (0.66 mole) of triethylamine in 500 ml of ethanol. An exothermic effect was observed and a white precipitate separated out. The mixture was stirred for a further 2 hours under reflux, concentrated to half in vacuo and introduced into 1 liter of ice water. The white precipitate was filtered off, dried over phosphorus pentoxide and recrystallized from about 300 ml of petroleum ether. 147 g (76% of theory) of 2-(3',4' -dichlorophenylthio)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 46° C were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccc(F)cc1
Product: CC(=O)NCCc1ccc(F)cc1

Procedure:
In close analogy to the procedure described above, 2-(4-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[CH:8](=O)[CH2:9][CH2:10]C>C(O)CCC>[CH2:1]([CH:3]([CH:6]([OH:7])[CH2:8][CH2:9][CH3:10])[CH:4]=[O:5])[CH3:2]
Reactant: CCCC=O
Reactant: CCC(CO)CO
Solvent: CCCCO
Product: CCCC(O)C(C=O)CC
Yield: 52.6 %

Procedure:
JP patent publication 1 299 240 discloses a process for the preparation of 2-ethyl-1,3-propane diol from n-butyraldehyde by aldol condensation by using alkali metal alkoxides as the catalyst. The reaction was performed in the presence of sodium methoxy in a butanol solution at 40° C. 2-Ethyl-3-hydroxyhexanal formed with a yield of 52.6%, and it was hydrogenated with Raney nickel at a temperature of 100° C. and a pressure of 50 atm.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:6][C:5]([F:24])=[CH:4][N:3]=1.[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:24][C:5]1[CH:6]=[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[C:2]([CH3:25])=[N:3][CH:4]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: O=C(Nc1cc2ccc(-c3cc(F)cnc3Cl)cc2cn1)C1CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ncc(F)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 90 °C
Yield: 51.1 %

Procedure:
A mixture of N-(7-(2-chloro-5-fluoropyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (105.4 mg, 0.3084 mmol), trimethylboroxine (129.0 uL, 0.9228 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (22.3 mg, 0.0315 mmol), and potassium carbonate (112.5 mg, 0.8140 mmol) in 1,4-dioxane (2.0 mL, 26 mmol) was heated at 90° C. for 26 hours. The reaction mixture was then diluted with dichloromethane, washed with water, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 50.6 mg (51%) of N-(7-(5-fluoro-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (Min)=3.972, M+H=322.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.19 (s, 1H), 8.52 (s, 2H), 8.12 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.86-7.67 (m, 2H), 2.47 (s, 3H), 2.08 (dd, J=12.4, 7.3 Hz, 1H), 0.86 (dd, J=9.3, 6.4 Hz, 4H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].CB1OB(C)OB(C)O1.[CH2:16](Cl)Cl.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([F:31])([F:30])([F:29])([F:28])[F:27])=[CH:22][C:21]=1Br>C(COC)OC.Cl[Pd]Cl.O>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([F:31])([F:30])([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH3:16]
Reactant: ClCCl
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1Br
Agent: Cl[Pd]Cl
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(S(F)(F)(F)(F)F)ccc1N
Temperature: 70 °C
Yield: 1724.8 %

Procedure:
A mixture of Cs2CO3 (794 g, 2.7 mol), dimethoxyethane (2 l), water (300 ml) and trimethylboroxine (50 percent solution in THF, 225 g, 0.9 mol) was heated to 70° C., PdCl2 (dppf). CH2Cl2 (37 g, 45 mmol) was added, and a solution of 4-amino-3-bromophenylsulfur pentafluoride (270 g, 0.9 mol) in dimethoxyethane (400 ml) was added dropwise within 2 h while the reaction mixture was heated to reflux. It was subsequently heated to reflux for a further 3 h and then cooled to room temperature, diluted with MTB (500 ml), filtered through a silica gel column (14×7 cm, 70-200 μm) and washed with MTB (2500 ml). The filtrate was concentrated under reduced pressure. 490 g of a black, semicrystalline mass were obtained and were subjected to a steam distillation. A total of 5.5 l of condensate was collected, from which the crystals of the product separated out. The condensate was extracted 3 times with MTB, and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. 4-Amino-3-methylphenylsulfur pentafluoride (181 g, 76%) was obtained as colorless crystals, m.p. 65-66° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:29][CH2:30][C:31]2[S:32][CH:33]=[C:34]([CH:36]([CH3:38])[CH3:37])[N:35]=2)=[CH:4][C:5]2[N:6]([CH:28]=1)[C:7](=[O:27])[C:8](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1)[N:10]=2.ClC(Cl)(Cl)[C:41]([N:43]=C=O)=[O:42].CO.C(Cl)(Cl)Cl.C([O-])=O.[Na+]>C(OCC)(=O)C>[NH2:43][C:41]([O:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]2[N:10]=[C:5]3[CH:4]=[C:3]([CH2:29][CH2:30][C:31]4[S:32][CH:33]=[C:34]([CH:36]([CH3:38])[CH3:37])[N:35]=4)[C:2]([F:1])=[CH:28][N:6]3[C:7](=[O:27])[C:8]=2/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=[O:42]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)c1csc(CCc2cc3nc(N4CCCC(O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1csc(CCc2cc3nc(N4CCCC(OC(N)=O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 137.6 %

Procedure:
The tert-butyl (E)-3-{7-fluoro-2-(3-hydroxypiperidino)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (48.0 mg, 0.0885 mmol) obtained in Example 156, (M) was dissolved in ethyl acetate (3 ml), added with trichloroacetyl isocyanate (0.052 ml, 0.442 mmol) and stirred at room temperature for 1 hour. The reaction mixture was added with methanol:chloroform (1:10, 10 ml) and concentrated, and the resulting residue was dissolved in a mixed solvent of methanol (3 ml) and distilled water (1 ml), added with sodium formate (12.0 mg, 0.177 mmol) and stirred overnight at room temperature. The solution was further added with sodium formate (12.0 mg, 0.177 mmol), stirred for 5 hours and then concentrated, and the resulting residue was purified by preparative TLC (chloroform:methanol=100:5) to obtain the title compound (71.3 mg, quantitative) as lyophilized product.