Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[N:12]([CH2:15][C:16]([O:18]C)=[O:17])[C:13](=[O:14])[N:5]([C:6]=23)[CH2:4][C:3]1=[O:20].[OH-].[Na+:22].Cl>CO>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[N:12]([CH2:15][C:16]([O-:18])=[O:17])[C:13](=[O:14])[N:5]([C:6]=23)[CH2:4][C:3]1=[O:20].[Na+:22]
Reactant: COC(=O)Cn1c(=O)n2c3c(cccc31)N(C)C(=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)Cn2c(=O)n(CC(=O)[O-])c3cccc1c32
Reaction time: 3 h

Procedure:
To a solution of methyl (6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate from Step A (225 mg, 0.817 mol) in MeOH (10 mL) was added 1.0 N sodium hydroxide (1.2 mL, 1.2 mmol). After 3 h, the reaction mixture was neutralized with 1 N aqueous HCl and concentrated to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH:9]([S:14]([OH:17])(=[O:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>CC(N(C)C)=O>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH:9]([S:14]([OH:17])(=[O:15])=[O:16])[CH2:10][C:11]([O:13][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29])=[O:12]
Reactant: O=C(O)CC(CN1C(=O)C=CC1=O)S(=O)(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: O=C(CC(CN1C(=O)C=CC1=O)S(=O)(=O)O)ON1C(=O)CCC1=O
Yield: 74.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-sulfobutanoic acid (110 mg, 0.418 mmol), EDC (240 mg, 1.25 mmol) and N-hydroxysuccinimide (58 mg, 0.504 mmol) was stirred in 10 ml of DMA for overnight, evaporated and purified on SiO2 chromatography eluted with CH3OH/CH2Cl2/HAc (100:900:1 to 100:600:1) to afford 112 mg (75%) of the title product. 1H NMR (DMF-d7) 6.93 (s, 2H), 4.06 (dd, 1H, J=4.8, 13.1 Hz), 3.80 (dd, 1H, J=10.7, 13.9 Hz), 3.35 (dd, 1H J=3.3, 17.8 Hz), 3.25 (m, 1H), 3.10 (dd, 1H, J=2.2, 16.4 Hz), 2.87 (m, 4H); 13C NMR 172.27, 170.88, 169.29, 135.55, 55.28, 40.22, 32.69, 26.66; ESI MS m/z−261.70 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[CH3:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([NH2:24])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[CH:4]=[N:24][C:13]1[C:14]([C:16]#[C:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:15][C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: Cc1ccc(N)c(C#Cc2ccccc2)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(N=CN(C)C)c(C#Cc2ccccc2)n1
Yield: 18.4 %

Procedure:
A solution of N,N-dimethylformamidedimethylacetal (80 μl, 0.60 mmol) and (6-methyl-2-phenylethynyl-pyridin-3-yl)amine (102 mg, 0.49 mmol) from Example 1, in toluene (1 ml) was heated for 20 h, at 80° C. The solvent was evaporated and the residue was purified by flash chromatography (hexane/ethyl acetate 4:1) to give 24 mg (0.09 mmol, 15%) of N,N-dimethyl-N′-(6-methyl-2-phenylethynyl-pyridin-3-yl)-formamidine as a yellow oil.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]1[CH:22]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](N)=[O:28])SS[CH2:19]1>CCCCCC>[C:27]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:18][CH2:19]/[CH:1]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NC(=O)CCCCC1CCSS1
Reactant: CCCCCCCCCCCCCCCCO
Solvent: CCCCCC
Product: CCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCC
Yield: 95 %

Procedure:
Preparation of hexadecyl cis-9-tetradecenoate, 4 was carried out according to the Scheme 1. Oleic acid methyl ester, 1 (12.0 g, 0.0314 mol) in dichloromethane (100 ml) was cooled to −78 degree. C and ozone gas was bubbled into the reaction mixture for 1 hr. After reaction, the reaction was quenched by adding dimethyl sulphide (DMS, 8 ml) and was stirred for 6 hr at 25° C. The solvents were removed under vacuum and the residue 2 thus obtained (4.25 g, 0.022 mol) was used directly for the preparation of cis-9-myristoleate, 3. n-Pentyl-triphenyl phosphonium salt (11.16 g, 0.027 mol) was taken in 50 ml of dry THF and cooled to 0° C. To this slurry, n-butyl lithium (17.0 ml, 1.6 M in hexane) was added, stirred the reaction mixture for 0.5 hr to obtain an orange solution. 1-Al-methyl nonanoate containing crude product 2 (5.0 g, 0.027 mol) dissolved in dry THF (20 ml) was added to the above contents slowly and allowed the reaction mixture to reach to 25 degree. C and then heated to reflux temperature to reflux for 4 hr. The reaction was monitored by TLC and after completion of the reaction, THF was removed from the reaction mixture under reduced pressure, and to the residue distilled water 825 ml) was added and extracted with ether (25 ml×3 times). The combined ether layer was dried over anhydrous sodium sulphate and solvent was removed and dried under vacuum to get the residue and was purified by column chromatography using hexane and ethyl acetate (98:2) as eluent to get cis-9-myristoleate, 3 (4.2 g, 0.0175 mol) in 65% yield with 66% purity by GC. cis-9-Myristoleate, 3 (4.2 g, 0.0175 mol) was enzymatically transesterified with cetyl alcohol (5.08 g 0.021-mol) in the presence of Lipozyme TL IM (0.930 g, 10 wt % of the total substrate) at 68° C. for 8 hr. The reaction was monitored by TLC and after completion of the reaction, hexane (50 ml) was added and the lipase was separated by filtration and the solvent was evaporated to get the crude product and was purified by column chromatography to obtain hexadecyl cis-9-tetradecenoate, 4 (7.48 g, 0.0166 mol) in 95% yield with 92% purity by GC. The structure of hexadecyl cis-9-tetradecenoate, 4 was confirmed by 1H NMR, IR, and GC-MS.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH:13]([CH2:15][NH:16][CH3:17])[CH2:14][C:3]1=2.C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25]=[C:26]=[O:27]>O1CCCC1>[CH3:24][NH:25][C:26](=[O:27])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[CH2:14][CH:13]([CH2:15][NH:16][CH3:17])[CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CN=C=O
Reactant: CNCC1Cc2c(n(C)c3ccc(O)cc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNCC1Cc2c(n(C)c3ccc(OC(=O)NC)cc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-4-methyl-2-[(methylamino)methyl]cyclopent[b]indol-7-ol (1.7 g, 0.007 mole) in 30 ml of tetrahydrofuran, was added milled K2CO3 (1.2 g, 0.01 mole), followed by methyl isocyanate (0.4 ml, 0.07 mole). After stirring at ambient temperature for two hours, the mixture was filtered, and the filtrate concentrated to a yellow oil (~2 g), which was dissolved in ethyl acetate then washed with water and then dried over anhydrous MgSO4. After filtering, the solvent was evaporated to afford a tan solid, ~1.0 g, which was eluted on a silica gel column with 5% methanol/dichloromethane via HPLC. The desired fraction was concentrated to a tan foam (0.8 g, m.p. ~50° C.), which was recrystallized from ethyl ether to give the product as a tan solid, 0.6 g, m.p. 216° C. (dec).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[N:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[N:11]=[N:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[C:23]([F:22])([F:33])[F:34])=[O:27])[CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: c1ccc2[nH]c(-c3ccc(N4CCNCC4)nn3)nc2c1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3nc4ccccc4[nH]3)nn2)CC1
Yield: 27 %

Procedure:
Following the procedure as described in Example 6, making variations only as required to use 2-(6-piperazin-1-ylpyridazin-3-yl)-1H-benzoimidazole in place of 2-(6-piperazin-1-ylpyridin-3-yl)-1H-benzoimidazole to react with 2-trifluoromethylbenzoyl chloride, the title compound was obtained as a white powder in 27% yield (0.122 g). 1H NMR (300 MHz, CDCl3) δ 13.25 (s, 1H), 8.16 (d, J=9.6 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.6 Hz, 2H), 7.54 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.42 (d, J=9.6 Hz, 1H), 7.22-7.13 (m, 2H), 3.87-3.56 (m, 6H), 3.26-3.12 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 165.1, 158.2, 148.1, 142.8, 142.5, 133.7, 133.4, 131.8, 128.4, 126.4, 125.4, 124.9, 124.4, 124.3, 123.9, 121.8, 120.8, 117.8, 112.4, 110.6, 44.8, 42.9, 42.7, 39.6. MS (ES+) m/z 453.3 (M+1).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[S:8])[NH:6][NH2:7])[CH:2]=[CH2:3].[CH2:9]([Cl:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>>[ClH:18].[C:12]1([C:10]2[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[N:6][NH2:7])[S:8][CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: C=CCNC(=S)NN
Product: C=CCn1c(-c2ccccc2)csc1=NN
Product: Cl

Procedure:
From 4-(2-propenyl)-3-thiosemicarbazide and phenacyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[C:8]=1[C:9]1[C:10](=[O:29])[N:11]([CH:26]([CH3:28])[CH3:27])[C:12](=[O:25])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:14]=1)(=[O:3])[CH3:2].[CH3:38][Mg]Cl.O.C(OCC)(=O)C>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[N:6][N:7]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[C:8]=1[C:9]1[C:10](=[O:29])[N:11]([CH:26]([CH3:28])[CH3:27])[C:12](=[O:25])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)[CH:14]=1)([CH3:38])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1cnn(-c2ccc(C#N)cc2)c1-c1cn(-c2cccc(C(F)(F)F)c2)c(=O)n(C(C)C)c1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1c(=O)c(-c2c(C(C)(C)O)cnn2-c2ccc(C#N)cc2)cn(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To a solution of 4-(4-acetyl-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 136) (28.2 mg) in tetrahydrofuran (1.0 ml) was added under ice-cooling methyl magnesium chloride (3.0 M tetrahydrofuran solution, 27.8 μl) dropwise and the resulting mixture was stirred under ice-cooling for one hour. To the resulting mixture was water (1 mL) followed by an addition of ethyl acetate (50 ml), and the mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-(2-hydroxypropan-2-yl)-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (4.3 mg) as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccnc1Br
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ncccc2C)cc1
Yield: 75.4 %

Procedure:
4-methylphenylboronic acid (20.0 g, 0.147 mol) was reacted with 2-bromo-3-methylpyridine (21.1 g, 0.123 mol) under standard Suzuki coupling condition. A small amount of unreacted 2-bromo-3-methylpyridine was removed via vacuum distillation. Purification via flash silica gel chromatography with a 1/99 to 7.5/92.5 EtOAc/hexane solvent gradient yielded 17.0 g of 2-(4-methylphenyl)-3-methylpyridine as a colorless liquid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])[CH2:2][CH2:3][CH3:4].[CH:16]([N:19]=[C:20]=[N:21][CH:22]([CH3:24])[CH3:23])([CH3:18])[CH3:17]>>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:10][CH3:11])[O:12][CH3:13])[C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:19][CH:16]([CH3:18])[CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCC[Si](OC)(OC)OC
Reactant: CC(C)N=C=NC(C)C
Product: CCCCN(CCC[Si](OC)(OC)OC)C(=NC(C)C)NC(C)C
Reaction time: 2 h

Procedure:
A mixture of 45 g of N-butyl-(3-(trimethoxysilyl)propyl)amine (0.191 mol) and of 28.95 g of diisopropylcarbodiimide (0.229 mol, 20% excess) was heated for 20 h at 120° C. (amine conversion of 93%). The final colorless mixture was devolatilized at 120° C. under 1 mbar for 2 h to give 67 g of a colorless, low-viscosity liquid corresponding to the expected guanidine, containing 4 wt % of the initial amine.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1(C=O)[CH:13]=[CH:12][C:11]2[CH2:10][N:9]([CH:14]3[CH2:16][CH2:15]3)[CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH2:5]1.C([Li])CCC>O1CCCC1>[CH:14]1([N:9]2[CH2:8][C:7]([CH3:17])([CH3:18])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:3]#[CH:2])[CH:5]=3)[CH2:10]2)[CH2:16][CH2:15]1
Reactant: CC1(C)CN(C2CC2)CC2=C1CC(C=O)(C=C(Br)Br)C=C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Temperature: -20 °C
Yield: 94.4 %

Procedure:
A stirred, cooled (−78° C.) solution of 6-(2,2-dibromo-vinyl)-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate 26, 0.18 g, 0.47 mmol) in tetrahydrofuran (2 mL) was treated with 1.6M solution of n-butyl lithium (0.6 mL, 0.96 mmol) under argon. The reaction mixture was allowed to warm to −20° C. over 1.5 h, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as an oil (0.1 g, 94%).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:20]>CN(C)C=O.O>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[CH:3][C:4]2=3)[C:12]1=[O:20]
Reactant: O=C1CCCc2[nH]ccc21
Reactant: O=C1Cc2ccccc2N1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1CCCc2[nH]ccc21
Temperature: 140 °C
Yield: 11.9 %

Procedure:
A mixture of 680 mg 1,5,6,7-tetrahydro-4H-indol-4-one and 1.33 g oxindole in 3 ml dimethylforamide was heated at 140° C. for 50 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water and then brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified on a silica gel column using hexanes/ethyl acetate as the eluent to provide 150 mg of 1′,5′,6′,7′-tetrahydro-1H-[3,4′]biindolyliden-2-one as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[N:23]=3)[N:16]=2)([OH:13])[CH2:9][CH2:8]1)=[O:6]>FC(F)(F)C(O)=O.O>[ClH:1].[Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([N:7]1[CH2:8][CH2:9][C:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[CH:26]=[CH:25][NH:24][N:23]=3)[N:16]=2)([OH:13])[CH2:11][CH2:12]1)=[O:6]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CC3(O)CCN(C(=O)c4cccc(Cl)c4F)CC3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cl
Product: O=C(c1cccc(Cl)c1F)N1CCC(O)(Cc2cccc(Nc3cc[nH]n3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
273 mg of 1-(3-chloro-2-fluorobenzoyl)-4-((6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidin-4-ol was dissolved in 3 ml of trifluoroacetic acid and 0.3 ml of water, followed by stirring the reaction mixture at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The resulting ethyl acetate layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1). The obtained free form was dissolved in 5 ml of ethyl acetate. 0.5 ml of 4 M hydrogen chloride in 1,4-dioxane was added to the solution at room temperature, followed by diluting with 5 ml of tert-butyl methyl ether. The precipitate was collected and washed with tert-butyl methyl ether to give the title compound as a white solid.
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=[CH:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:35]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>>[C:12]([O:11][C:9]([NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([Cl:35])[CH:3]=[CH:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](O)CC1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a mixture of trans-1-hydroxy-4-(tert-butoxycarbonylamino)-2-cyclohexene (2.93 g, 13.8 mmol) in hexachloroacetone (70 mL) was added triphenylphosphine (7.51 g, 28.6 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the thus obtained oil was purified by column chromatography on silica gel (10:1 hexanes-ethyl acetate) and provided 1.98 g (62%) of cis-1-(tert-butoxycarbonylamino)-4-chloro-2-cyclohexene as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:3]2[S:26][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][CH:2]=2)[CH2:6][CH2:7]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CBr)C1CCN(C(=O)c2ccccc2)CC1
Solvent: CCO
Product: O=C(c1ccccc1)N1CCC(c2cnc(-c3ccccc3)s2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
To 150 mg of 2-bromo-1-(1-benzoyl-4-piperidyl)-1-ethanone in 6 ml of EtOH was added 66 mg of thiobenzamide. The reaction was stirred at 80° C. for 2 hours. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography with 50% EtOAc in hexane to give 55 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][S:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: ClCc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CSCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 3-bromo-5-(chloromethyl)pyridine (from example 199, (1.2 g, 5.8 mmol) in acetonitrile (15 mL) was added K2CO3 (0.97 g, 7.0 mmol) followed by methyl 2-mercaptoacetate (0.57 mL, 6.4 mmol). The resulting solution was stirred at room temperature for 16 h. After this time, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water. The organic portion was dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to yield methyl 2-((5-bromopyridin-3-yl)methylthio)acetate (1.2 g, 80% yield). LCMS Method Y: retention time 1.66 min; [M+1]=276.0.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].[Br:9][C:10]1[C:11](Cl)=[N:12][C:13]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[N:21][CH:22]=2)=[N:14][CH:15]=1>N1C=CC=CC=1>[Br:9][C:10]1[C:11]([O:5][CH:3]([CH3:4])[CH:2]([OH:6])[CH3:1])=[N:12][C:13]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[N:21][CH:22]=2)=[N:14][CH:15]=1
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(O)C(C)Oc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
270 mg (1.5 mmol) of (2R, 3R)-(−)-2,3-butanediol is dissolved in 3 ml of pyridine and mixed with 30 mg (0.69 mmol) of sodium hydride. It is allowed to stir for 15 minutes at room temperature and then 110 mg (0.3 mmol) of 5-(5-bromo-4-chloro-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide is added. After 1 hour at room temperature, it is stirred for 4 more hours at 50° C. Concentration by evaporation and flashing with dichloromethane/MeOH 4:1 yields 42 mg of 5-[5-bromo-4-(2-hydroxy-1-methyl-propoxy)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide: (34% of theory)°
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24]I)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[F:27][C:28]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][N:30]3[CH2:31][CH2:32][C:28]([F:33])([F:27])[CH2:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: FC1(F)CCNC1
Reactant: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reaction time: 120 h
Yield: 27.8 %

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (91 mg, 0.2 mmol) in dry CH2Cl2 (2 mL) was added to 3,3-difluoropyrrolidine hydrochloride (143 mg, 1 mmol), DIPEA (0.2 mL, 1.1 mmol) was added and the reaction stirred for 5 days. The resultant residue was purified using chromatography (silica gel, gradient 20 to 50% ethyl acetate/isohexane, followed by preparative HPLC to provide Compound IIv as a white solid (24.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=[C:21]([Cl:29])[N:20]=1>CN(C)C=O>[ClH:29].[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21]2[N:20]=[C:19]([N:10]3[CH2:11][CH2:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:9]3)[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[N:22]=2)=[CH:4][CH:3]=1
Reactant: Clc1nc2c(c(N3CCc4ccccc4C3)n1)CCCC2
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cl
Product: Fc1ccc(Nc2nc3c(c(N4CCc5ccccc5C4)n2)CCCC3)cc1
Yield: 50.3 %

Procedure:
After 4-fluoroaniline(0.60 ml, 6.3 mmol) was added to a mixture solution of 4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloro-5,6,7,8-tetrahydroquinazoline(0.90 g, 3.0 mmol) and dimethylformamide(5 ml), 0.62 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:33]1[CH:34]=[CH:35][C:36]([C:41]([F:44])([F:43])[F:42])=[C:37]([CH:40]=1)[C:38]#[N:39].C([Mg]Cl)(C)C.[Cl-].[Li+].C([Mg]Cl)(C)C>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([OH:25])[C:33]3[CH:34]=[CH:35][C:36]([C:41]([F:42])([F:43])[F:44])=[C:37]([CH:40]=3)[C:38]#[N:39])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(I)ccc1C(F)(F)F
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)c(C#N)c1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 5-iodo-2-(trifluoromethyl)benzonitrile. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride-complex in tetrahydrofurane is used instead of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane.