Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:34])=[C:18]([NH:20][C:21](=[O:33])[CH2:22][C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)[CH:19]=1.O[CH2:36][CH2:37][CH2:38][N:39](C)[C:40](=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:67]>O1CCCC1.CO>[ClH:67].[CH3:40][NH:39][CH2:38][CH2:37][CH2:36][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:34])=[C:18]([NH:20][C:21](=[O:33])[CH2:22][C:23]23[CH2:32][CH:27]4[CH2:26][CH:25]([CH2:31][CH:29]([CH2:28]4)[CH2:30]2)[CH2:24]3)[CH:19]=1
Reactant: Cc1ccc(O)cc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CNCCCOc1ccc(C)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 72 h

Procedure:
Diethyl azodicarboxylate (0.50 ml) was added to a solution of N-(5-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.50 g, Example 12), tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (0.60 g, J. Org. Chem., 1988, 53(10), 2229) and triphenylphosphine (0.88 g) in tetrahydrofuran (5 ml). After stirring for 19 hours at room temperature further triphenylphosphine (0.90 g) and diethyl azodicarboxylate (0.50 ml) were added. After stirring for 4 hours at room temperature further triphenylphosphine (0.90 g) and diethyl azodicarboxylate (0.50 ml) were added and the reaction mixture was stirred for 3 days. The reaction was then concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give material that was further purified by chromatography over a Dynamax® column using a Gilson automated chromatography machine eluting with iso-hexane:ethyl acetate (4:1) to give the Mitsunobu reaction product (0.29 g) which was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (10 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was then concentrated under reduced pressure to give the title compound as a yellow solid (0.13 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:19][C:13]2[N:8]3[CH:9]4[CH2:12][CH:11]([C:5]5[CH:4]=[C:3]([F:22])[C:2]([Br:1])=[CH:21][C:6]=5[C:7]3=[N:15][C:14]=2[C:16]([NH2:18])=[O:17])[CH2:10]4)[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(Cc2c(C(N)=O)nc3n2C2CC(C2)c2cc(F)c(Br)cc2-3)CC1

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with N-acetylpiperazine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 3-((4-acetylpiperazin-1-yl)methyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 41 mg (41%) of 3-[(4-acetylpiperazin-1-yl)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=480.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:10]1([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[NH2:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(N)c(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a degassed solution of 2-bromo-4-methylbenzenamine (0.301 g, 1.618 mmol), phenyl boronic acid (0.296 g, 2.427 mmol), and tetrakistriphenylphosphine palladium(0) (0.187 g, 0.162 mmol) in DME (8 mL) was added 2M sodium carbonate solution (3 ml, 6 mmol) and the mixture was stirred for 16 h at 80° C. Water (30 ml) was added and the product was extracted with EtOAc (2×30 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated and purified by silica gel chromatography to provide 2-phenyl-4-methylbenzenamine as a thick syrup (0.22 g, 75% yield). 1H NMR (400 MHz, CDCl3): δ 7.47-7.41 (m, 4H), 7.36-7.32 (m, 1H), 6.99-6.96 (m, 2H), 6.71 (d, J=8.0 Hz, 1H), 2.28 (s, 3H); MS (ESI) m/z: 184.2 (M+H+).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]([CH2:15][C:16]1[N:17]=[N:18][N:19]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[C:23]([F:34])[CH:22]=2)[CH:20]=1)=[N+:13]=[N-:14].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[N:12]([CH2:15][C:16]1[N:17]=[N:18][N:19]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([N:28]3[CH2:33][CH2:32][S:31](=[O:6])[CH2:30][CH2:29]3)=[C:23]([F:34])[CH:22]=2)[CH:20]=1)=[N+:13]=[N-:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCS(=O)CC3)c(F)c2)nn1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
m-Chloroperoxybenzoic acid (75%, 545 mg, 2.36 mmol) was added to a solution of 4-[4-(4-azidomethyl-[1,2,3]triazol-1-yl)-2,6-difluoro-phenyl]-thiomorpholine (800 mg mmol), obtained in Example 13, in dichloromethane (10 mL) at 0° C. and allowed to stir for 1 h. The reaction mixture was then diluted with dichloromethane (20 mL) and a solution of sodium sulfite was added. Aqueous layer was separated and the dichloromethane layer was washed with water followed by brine and dried over sodium sulfate. Removal of volatiles produced the title sulfoxide (800 mg, 95%).
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:18][N:17]=1.[I:29]I>C1COCC1>[I:29][C:20]1[C:19]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:18][N:17]=[C:16]([O:15][CH3:14])[CH:21]=1
Reactant: COc1ccc(OC2CCCCO2)cn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(I)c(OC2CCCCO2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., 13.6 ml (90.1 mmol, 1.2 eq.) of 1,2-bis(dimethylamino)ethane and 54.0 ml (86.4 mmol, 1.15 eq.) of n-butyllithium were added to a solution of 16.2 g (75.1 mmol) of 2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine in 250 ml of THF, and the mixture was stirred at −78° C. for 1 h. 24.8 g (97.6 mmol, 1.3 eq.) of iodine were then added, and the reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to RT overnight. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium thiosulphate solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 25.1 g (purity 82%, 82% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([C:25]#[N:26])(C)[C:19](OCC)=O)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH:18]([CH3:19])[C:25]#[N:26])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C#N)c1cccc2c(-c3ccc(Cl)cc3)nccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C#N)c1cccc2c(-c3ccc(Cl)cc3)nccc12
Yield: 62.3 %

Procedure:
Ethyl 2-[1-(4-chlorophenyl)isoquinolin-5-yl]-2-cyanopropionate (1.0 g) was heated under reflux together with 40 ml of ethanol, 0.20 g of sodium hydroxide and 2 ml of water. After the reaction, the reaction mixture was concentrated under reduced pressure. The resulting oily product was extracted with ether, and dried. The solvent was distilled off, and the residue was recrystallized from ether-hexane to afford 0.5 g of 2-[1-(4-chlorophenyl)isoquinolin-5-yl]propionitrile as colorless needles having a melting point of 127.5° to 130° C.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cnc3ccccc3c2)CCN(C)C1

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (260 mg, 1.160 mmol), 3-bromoquinoline (200 mg, 0.961 mmol), TBAF.3H2O (1.1 g, 3.492 mmol) and dichloro bis(triphenylphosphine) palladium (II) (41 mg, 0.058 mmol) was stirred at 85° C. for 10 min. The reaction mixture was diluted with water and extracted with EtOAc (4×30 mL). The combined organic layer was washed with water (4×30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using neutral alumina and 0.5% MeOH-DCM to yield 2,8-dimethyl-5-quinolin-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 9.0 (s, 1H), 8.25 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.5 (d, 1H), 7.2 (s, 1H), 7.1 (d, 1H), 3.62 (s, 2H), 3.0 (t, 2H), 2.7 (t, 2H), 2.6 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Br[CH2:30][CH2:31][C:32]1[C:33]([CH3:38])=[N:34][NH:35][C:36]=1[CH3:37]>ClCCl>[CH3:38][C:33]1[C:32]([CH2:31][CH2:30][O:17][C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[S:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=4[C:2]([NH2:1])=[N:3][C:4]=3[CH:5]=2)=[C:36]([CH3:37])[NH:35][N:34]=1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: Cc1n[nH]c(C)c1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCCc4c(C)n[nH]c4C)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
A mixture of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (245 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 4-(Bromoethyl)-3,5-dimethyl-1H-pyrazole (223 mg, 1.1 mmol) was added in portions over a period of 30 minutes. The reaction mixture was stirred for 20 minutes and then the heat source was removed. The reaction mixture was diluted with water (250 mL), stirred overnight, and then filtered. The isolated solid was rinsed with water and then dried to provide a tan powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-30% CMA in chloroform 700 mL and then with 30% CMA in chloroform over 200 mL. The resulting solid was recrystallized from 50:1 acetonitrile:methanol (40 mL) to provide 205 mg of 7-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-2-ethylthiazolo[4,5-c]quinolin-4-amine as an off white solid, mp 195.0-197.0° C. MS (APCI) m/z 368 (M+H)+; Anal. calcd for C19H21N5OS: C, 62.10; H, 5.764; N, 19.06. Found C, 61.95; H, 5.53; N, 19.09.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]3[C:18]4[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:19]=4[NH:20][C:16]=3[C:15](=O)[NH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:38]>>[Cl:38][C:15]1[C:16]2[NH:20][C:19]3[N:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:18]=3[C:17]=2[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)c1cccc(-c2c[nH]c(=O)c3[nH]c4ncc(C)cc4c23)c1
Solvent: CN(C)c1ccccc1
Product: CCS(=O)(=O)c1cccc(-c2cnc(Cl)c3[nH]c4ncc(C)cc4c23)c1
Yield: 69 %

Procedure:
Compound 31 (50 mg, 0.136 mmol) stirred in POCl3 (2 mL) with dimethylaniline (0.1 mL) at 108° C. under nitrogen for 16 h. The solution was concentrated and dissolved in CH2Cl2. Ice and saturated NaHCO3 solution were added, and organics were extracted (2×) with CH2Cl2, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (3% MeOH/CH2Cl2) gave 36 mg (69%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD-d4/CDCl3): δ 8.46 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 8.01 (d, 1H, J=8.0 Hz), 7.89 (t, 1H, J=8.0 Hz), 7.84 (s, 1H), 7.76 (s, 1H), 3.28 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.31 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C19H16ClN3O2S, 386, 388; found 386, 388.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(3-bromophenyl)butan-1-ol (5 g) (WO 0266422 A1) in dry DMF was treated with imidazole (1.8 g) and tert-butyldiphenylsilyl chloride (7.2 g) and stirred at room temperature for 16 h. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with 2M HCl, water, sat. NH4Cl(aq), water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, Gradient between cyclohexane and cyclohexane-EtOAc (5:1) to give the title compound. LCMS RT=4.82 min
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-chloro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=363.1 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl[C:24]([O:26][CH2:27][Cl:28])=[O:25]>ClCCl>[C:24](=[O:25])([O:22][CH2:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]1)[O:26][CH2:27][Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)OCCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (3.22 ml) was added to an ice-cold solution of 2-(1-(tert-butoxycarbonyl)-4-piperidyl)-ethanol (7.6 g) in dichloromethane (33 ml) followed by chloromethyl chloroformate (3.23 ml) at such a rate that the temperature was kept below 10° C. After stirring overnight at room temperature the reaction mixture was washed twice with 0.5 M HCl followed by water and aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:15]1[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]1)[CH:5]=[O:6]
Reactant: Cc1c[nH]cn1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C=O)cc2F)cn1
Temperature: 90 °C
Reaction time: 6 h
Yield: 17.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (40.0 g) in DMF (533 mL), 4-methylimidazole (46.4 g) and potassium carbonate (78.0 g) were added at room temperature, and the reaction solution was stirred at 90° C. for six hours. The reaction solution was left to cool to room temperature. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with tert-butyl methyl ether to obtain 10.1 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].O.[NH2:10][NH2:11]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:10][NH2:11])[NH2:8]
Reactant: N#Cc1ccccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN=C(N)c1ccccn1

Procedure:
A solution of pyridine-2-carbonitrile 20 g (192 mmol) and hydrazine hydrate (3 Eq.) in ethanol (50 mL) was stirred at room temperature for 18 hrs. The reaction mass was then diluted with water, extracted with ethyl acetate, and the organic portion dried (Na2SO4) and concentrated in vacuo to yield the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[OH:26].ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]2([CH3:25])[O:35][CH2:24]2)[C:3]=1[OH:26]
Reactant: C=C(C)Cc1c(O)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2CC2(C)CO2)c1=O
Temperature: 25 °C
Yield: 88.4 %

Procedure:
In 500 ml of chloroform, 50 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2 -methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved, to which 30.0 g of m-chloroperbenzoic acid was added, and the reaction was effected at 60° C. for 4.5 :hours. After completion of the reaction, the reaction mixture was cooled to room temperature and subjected to fractionation with a separatory funnel using chloroform and an aqueous solution of sodium sulfite. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then water, dried and concentrated. The residue was subjected to recrystallization, which afforded 46 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2,3-epoxy-2-methylpropyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:37])[C:35]=1[OH:36].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:31]=[C:30]([F:29])[C:35]([OH:36])=[C:34]([F:37])[CH:33]=1
Reactant: OB(O)c1cc(F)c(O)c(F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(F)c(O)c(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 15.2 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (260 mg, 0.59 mmol) was treated with (3,5-difluoro-4-hydroxyphenyl)boronic acid (154 mg, 0.89 mmol), sodium carbonate (2 M, 1.33 mL, 2.66 mmol) and 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (17 mg, 0.03 mmol) according to the method described in the Preparation 17. The residue was purified using SP1® Purification System (0% to 60%, hexane-ethyl acetate) to give 44 mg (15% yield) of the title compound as a white solid. Purity 95%.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1ccc(Cl)cc1
Reactant: Oc1ccc(S)cc1
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(Cl)cc1
Yield: 97 %

Procedure:
Ethyl(4-chlorophenyl)[(4-hydroxyphenyl)sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo(4-chlorophenyl)acetate (16.5 g, 59.6 mmol) and 4-mercaptophenol (7.5 g, 59.6 mmol); 18.8 g white solid. mp: 63° C.; Yield 97%; MS: 321.3 (M−H)−
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:10]2[S:14][C:13]([N:15]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:16][C@@H:17]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[NH2:9].[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>C1COCC1>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([C:10]3[S:14][C:13]([N:15]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:16][C@@H:17]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=4)=[N:12][N:11]=3)[CH:6]=[CH:7][C:8]=2[NH:9][C:44]1=[O:45]
Reactant: CNc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccc(-c3nnc(N(C[C@H](Cc4ccc(C(F)(F)F)cc4)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s3)cc21
Temperature: 70 °C
Reaction time: 10 h

Procedure:
The above mentioned crude tert-butyl (S)-1-(5-(3-(methylamino)-4-aminophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate was dissolved in 150 mL THF in a round bottom flask. To this flask was added a 50 mL THF solution of 1,1′-carbonyldiimidazole (1.37 g, 8.45 mmol). The mixture was stirred at 70° C. for 10 hours. After removing the solvent under reduced pressure, the remaining residue was mixed with 200 mL EtOAc. The organic solution was washed with water, three times with saturated ammonium chloride, and dried over sodium sulfate. After removing the solvent, the remaining residue was subjected to silica gel column chromatograph separation using 40% EtOAc in hexane as the eluant. There were two very close major spots on TLC (Rf=0.16, 0.17). The pure fractions for the bottom spot were combined. After removing the solvent, tert-butyl (S)-1-(5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.36 g) was obtained as a tan solid. LCMS (API-ES) m/z (%): 649.3 (100%, M++H); 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (s, 9H) 1.42 (s, 9H) 2.83 (m, 1H) 2.98 (m, 1H) 3.40 (s, 3H) 3.93-4.09 (m, 1H) 4.21-4.44 (m, 2H) 4.97-5.13 (m, 1H) 7.05 (d, J=8.02 Hz, 1H) 7.32 (d, J=7.82 Hz, 2H) 7.50 (m, 3H) 7.60 (s, 1H) 9.24 (s, 1H).