Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:9]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:10]#[N:11])[CH2:7][CH3:8].[OH2:18]>C(OCC)C>[CH2:15]([C:9]([CH2:6][CH2:7][CH3:8])([CH2:12][CH2:13][CH3:14])[C:10]([NH2:11])=[O:18])[CH2:16][CH3:17]
Reactant: O
Reactant: CCCC(C#N)(CCC)CCC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCC(CCC)(CCC)C(N)=O
Temperature: 10 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
In a 2-liter flask an 80% aqueous solution of 550 g of sulphuric acid was placed. While stirring, 110 g (0.66 mol) of tri-n-propylacetonitrile were added over a period of 20 minutes and at room-temperature. The temperature of the reaction medium rose to 80° C after which it was brought up to 105°-110° C for 6 hours. The solution was then cooled to 10° C and slowly poured into iced water (1000 g of purified water and 200 g of ice.) A pasty precipitate gradually formed as the solution was added to the iced water. As soon as the operation was finished, the mixture was stirred for 15 minutes and the precipitate centrifuged out and taken up twice in 350 g of ethyl ether. The ethereal solution was first washed twice with 200 g of water containing 10% of sodium bicarbonate and then twice with 250 g of water. The mixture was dried for 24 hours over 125 g of anhydrous sodium sulphate after which the sodium sulphate was centrifuged out. The ether was then eliminated by means of a rotatory evaporator which provided an oil which crystallized into fine needles which were left under vacuum until a constant weight was obtained. By this means, 113 g of crude tri-n-propylacetamide were obtained which represents a yield of 92.6%. The crude product was then dissolved by heating in 150 g of petroleum ether. After dissolution, 1.15 g of CECA WSL black was added and the mixture refluxed for 30 minutes. The black was then filtered off while the mixture was still hot. The filtrate was cooled to -15° C for 3 hours after which the precipitate which formed was centrifuged out and dried for 24 hours in a drying-oven at 40° C under 20 mm. Hg vacuum. In this way, 98.5 g of pure tri-n-propylacetamide were obtained which represents a yield in pure product of 87.1%. M.P. 69° C.
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[C@@H:31]([CH2:32][CH2:33][C@@H:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[OH:35])[C:30](=[O:43])[N:29]2[C:44]2[CH:49]=[CH:48][C:47](I)=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C@@H:9]1[O:17][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:51]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[C:52]#[CH:53]>CN(C=O)C.[Cu](I)I>[O:8]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[C@@H:31]([CH2:32][CH2:33][C@@H:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[OH:35])[C:30](=[O:43])[N:29]2[C:44]2[CH:49]=[CH:48][C:47]([C:53]#[C:52][CH2:51][NH:54][S:55]([CH3:58])(=[O:57])=[O:56])=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C@@H:9]1[O:17][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: C#CCNS(C)(=O)=O
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(I)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CCNS(C)(=O)=O)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
Triethylamine (0.07 mL, 0.502 mmol) was added to a stirred solution of 4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-iodophenyl)-4-oxoazetidin-2-yl]phenyl methyl β-D-glucopyranosiduronate (i-7) (0.050 g, 0.071 mmol), N-prop-2-yn-1-ylmethanesulfonamide (i-5) (0.014 g, 0.105 mmol), tetrakistriphenylphosphine palladium(0) (0.012 g, 0.010 mmol) and copper iodide (0.005 g, 0.026 mmol) in DMF (0.5 mL) under a nitrogen atmosphere and the resulting solution aged at room temperature for 18 h. The volatiles were evaporated in vacuo and the crude residue purified by flash chromatography on silica gel (gradient elution; 0-25% methanol/methylene chloride as eluent) to afford the title compound; m/z (ES) 713 (MH+), 505.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[C:20]2[CH2:25]O)=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10])([O-:3])=[O:2].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[C:20]2[CH2:25][N:31]2[C:30](=[O:32])[C:29]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]3[C:27]2=[O:37])=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, a mixture of 5-nitro-2'-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 5-nitro-2'-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.P(Br)(Br)[Br:12].O>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=1[F:10]
Reactant: BrP(Br)Br
Reactant: OCc1c(F)cncc1F
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1cncc(F)c1CBr
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of (3,5-difluoropyridin-4-yl)methanol (3.5 mmol) in anhydrous chloroform (15 mL) was added dropwise a solution of phosphorus tribromide (330 μL, 3.5 mmol) in anhydrous chloroform (5 mL) at 0° C. The mixture was stirred for 6 hours at room temperature. Water was added, and the reaction was extracted 3 times with dichloromethane. The combined organic phases were washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 4-(bromomethyl)-3,5-difluoropyridine was obtained as pale yellow solid (600 mg, 83% yield for 2 steps) and used in the next step without purification; 1H NMR (400 MHz, MeOd4): δ 4.59 (s, 2H), 8.42 (s, 2H).
Reaction SMILES: NC(=O)[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]C(C)C.NCC[C:42]([NH2:44])=[O:43]>>[NH2:44][C:42](=[O:43])[CH2:4][CH2:3][NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCC(N)=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NCCC(N)=O)C(C)(C)C)C1

Procedure:
Compound 73 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with 3-aminopropanamide. LCMS (+ESI) m/z=495.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.424 g. of pelargonic acid chloride as in Example 1. The 0.722 g. of yellow crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.617 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl nonanoate obtained melts at 43.2°-43.6° and has a clearing point of 74.0°. The compound is smectic up to 61.3°. UV (EtOH): ε272 = 26,900.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Br-].[CH3:13][OH:14]>>[O:10]1[CH:8]([CH:7]([O:14][CH3:13])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9]1
Reactant: CO
Reactant: OCC=Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Product: COC(c1ccccc1)C1CO1

Procedure:
Electrolyte: 300 g (2.239 moles) of 3-phenyl-2-propen-1-ol, 60 g of NaBr, and 2,640 g of methanol
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[N:2]1.[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][CH2:6][C:4]1[N:3]=[N:2][S:1][CH:5]=1
Reactant: O=Cc1csnn1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(CNCc2csnn2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3-thiadiazole-4-carboxaldehyde (750 mg, 6.57 mmol) and 2,4-dimethoxybenzylamine (1086 μl, 7.23 mmol) in 1,2-dichloroethane (13.1 mL) at 0° C. was added molecular sieves (powdered, 4 A) (2.50 g, 6.57 mmol) followed by sodium triacetoxyborohydride (1950 mg, 9.20 mmol). The reaction was allowed to warm to room temperature with stirring overnight. Then, the resulting suspension was poured into dichloromethane (75 mL) and aqueous sodium hydrogen carbonate (saturated, 75 mL). The layers were mixed and then filtered through celite. The aqueous layer was then extracted with dichloromethane (3×50 mL) and the combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes+1% triethylamine gradient) to afford the title compound as a pale yellow liquid. LRMS (APCI) calculated for C12H16N3O2S [M+H]+, 266.1. found 266.1.
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>ClCCl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1
Reactant: Brc1nsc2nc3ccccc3n12
Reactant: Nc1ccccn1
Solvent: ClCCl
Product: c1ccc(Nc2nsc3nc4ccccc4n23)nc1
Reaction time: 48 h
Yield: 83.1 %

Procedure:
To a cooled solution of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (0.30 g, 1.17 mmol) in 15 mL of dichloromethane, 2-aminopyridine (0.276 g, 2.93 mmol) was added dropwise and the mixture was allowed to stir for 48 h. The reaction mixture wad diluted with 100 mL of dichloromethane and washed with water (2×30 mL) and then brine (1×25 mL). The organic layer was dried over magnesium sulfate and evaporated to give a yellow solid (0.26 g, 83%) 1H-NMR (CDCl3) δ 6.59 (apparent 5, 1H, pyr-H), 7.12 (apparent br. d, 1H, pyr-H), 7.28 (t, 1H, ArH), 7.38 (t, 1H, ArH), 7.51 (m, 2H, ArH & pyr-H), 7.70 (d, 1H, ArH), 8.28 (d, 1H, pyr-H); m.p. 155.5-157° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[F:13][C:14]1[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][C:19]=1F>CCOC(C)=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:19]1[CH:18]=[CH:17][C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:14]=1[F:13])[CH3:2]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 107.9 %

Procedure:
To a solution of diethylamine (2.53 g, 34.59 mmol) and Et3N (3.82 g, 37.75 mmol) in EtOAc (40 mL) was added 3,4-difluoronitrobenzene (5.00 g, 31.43 mmol) dropwise over a period of 30 min in an ice bath. Upon the end of addition the reaction was warmed to rt slowly, and solid was precipitated out. The mixture was filtered. The filter cake was washed with an appropriate amount of water, and dried in vacuo to obtain the 1st crop of product. The filtrate was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (7.20 g, 99%).
Reaction SMILES: CN(C)C=O.Cl.[NH:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([OH:20])[CH2:16][C:17]([NH2:19])=[O:18])[C:8]([NH2:10])=[NH:9].[C:21]([Cl:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[ClH:29].[NH:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][C:17]([NH2:19])=[O:18])[C:8]([NH2:10])=[NH:9]
Reactant: N=C(N)NCCCC[C@H](O)CC(N)=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)NCCCC[C@@H](CC(N)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into 2.5 ml of dimethylformamide, was dissolved 2.09 of (S)-7-guanidino-3-hydroxyheptanamide hydrochloride followed by 1.7 ml of pyridine. To the solution, while being cooled in ice, was added slowly and dropwise 2.6 ml of benzoyl chloride. The mixture was stirred for 30 minutes while cooling in ice and for further two hours at room temperature. The reaction mixture was diluted with 20 ml of ice water, the separated oily layer was separated, and the aqueous layer was admixed with 600 mg of sodium chloride. The aqueous layer was passed through a column of Diaion® HP-20 which had been equilibrated with 0.5 M aqueous sodium chloride solution, and the column was washed successively with 0.5 M, 0.2 M and 0.1 M aqueous sodium chloride solutions, and with water. The fractions eluted with 20 to 40% (v/v) aqueous methanol were collected and concentrated under reduced pressure to yield 820 mg of (S)-7-guanidino-3-benzoyloxyheptanamide hydrochloride in oily form. NMR: 1.4-2.0 (CH2 x3), 2.65 (CH2), 3.17 (CH2), 5.50 (CH), 7.2-8.1 (COC6H5).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3/[C:20](=[N:29]\[O:30][CH3:31])/[C:21](OCCCCC)=[O:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH2:33].O>O1CCCC1>[CH3:32][NH:33][C:21](=[O:22])[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:12][C:9]1[N:10]=[CH:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[N:29][O:30][CH3:31]
Reactant: CN
Reactant: CCCCCOC(=O)/C(=N/OC)c1ccccc1COc1ncn(-c2ccccc2)n1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
1.5 g (3.6 mmol) of the pentyl ester from Example 13 were dissolved in 50 ml of tetrahydrofuran, and the mixture was treated with 10 ml of 40% strength aqueous monomethylamine solution and stirred at room temperature for 16 hours. It was then treated with water, extracted with methyl tert-butyl ether, and the organic phase was washed with water, dried over sodium sulfate and concentrated in a rotary evaporator. As a residue, 1.1 g (86% yield) of the title compound remained as a yellow oil.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1cc(C2(O)CCC(=O)CC2)cn1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:24])([CH3:23])[C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:24])([CH3:23])[C:9]2=[S:35])=[CH:4][CH:3]=1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound of Example 9, 182 mg) in dioxane (10 mL) was added Lawesson's reagent (202 mg), and the mixture was stirred at room temperature for 2 hours and then stirred at 40° C. for 24 hours. The reaction mixture was diluted with chloroform and the mixture was filtered through a NH-silica gel pad and washed with ethyl acetate. The filtrate and the washings were combined and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=19/1→3/2) to give N-[4-(4-fluorophenyl)-2,2-dimethyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (25 mg) as a yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[N:30]([CH2:36][CH2:37][O:38][CH3:39])[C:29]=2[CH:40]=1>>[F:19][C:18]1[C:9]([NH:8][C:6]2[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=[C:2]([NH:24][C:25]3[CH:26]=[CH:27][C:28]4[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[N:30]([CH2:36][CH2:37][O:38][CH3:39])[C:29]=4[CH:40]=3)[N:7]=2)=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: COCCN1C(=O)CCCc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3)ncc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide and 8-amino-1-(2-methoxyethyl)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one in an analogous manner to Example 195 (microwave: 120° C., 2 hours) to afford a white solid (30 mg, 50%). Mp: 142-4° C. LCMS (m/e) 547 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.03 (s, 1H), 8.35 (s, 1H), 7.56 (s, 1H), 7.47 (br s, 1H), 7.36 (m, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 7.01 (br s, 2H), 3.40 (m, 2H), 3.26 (s, 3H), 2.94 (d, J=5 Hz, 3H), 2.66 (br m, 2H), 2.23 (br s, 2H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:39][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCC2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (49%).
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][NH:20][C:21]2(C(N)=O)[CH2:25][NH:24][CH:23]=[N:22]2)=[CH:11][CH:10]=1.CO>ClCCl>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][N:20]2[C:21]3[N:22]=[CH:23][NH:24][C:25]=3[C:4](=[O:5])[NH:6][C:7]2=[S:8])=[CH:11][CH:10]=1
Reactant: CCOC(=O)N=C=S
Reactant: NC(=O)C1(NCc2ccnc3ccccc23)CNC=N1
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(=S)n(Cc2ccnc3ccccc23)c2nc[nH]c12
Temperature: 25 °C
Yield: 9 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.5 ml, 4.18 mmol) was added to a solution of 4-[(quinolin-4-ylmethyl)amino]-1H-imidazole-4-carboxamide (0.93 g, crude material from Example 24(a)) dissolved in anhydrous dichloromethane (10 mL) and methanol (5 mL) mixture. After o.n. (over night) at r.t., the solution was concentrated in vacuo and the residue was dissolved in 1N NaOH solution (30 mL) and refluxed for 3.5 h. After cooling to r.t., the pH was adjusted to ˜6.5 with 2 N HCl. The solid that formed was collected by filtration and dried generating 0.35 g of crude material. A portion of the solid (150 mg) was purified by preparative HPLC, and the solid obtained was washed with dichloromethane and ether, generating 25.9 mg (9% yield over two steps) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[C:4]=1[C:5](OC)=[O:6].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>O1CCCC1.CN(C=O)C>[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]2[C:4]=1[C:5](=[O:6])[N:15]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)[CH2:2]2)#[N:14]
Reactant: COC(=O)c1c(C#N)cccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3cccc(C#N)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 6C (300 mg) in tetrahydrofuran (2 mL) and N,N′-dimethylformamide (2 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (320 mg,) in N,N′-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) at −40° C. The solution was warmed to ambient temperature over 2 hours, and stirred for 16 hours. The solvent was removed, and the concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 80% ethyl acetate in hexanes.