Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][S:9]2(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[CH2:19][CH2:18]1)=[O:16].[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1.Cl>N1C=CC=CC=1>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([C:15]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH2:10][S:9]3(=[O:14])=[O:13])=[CH:7][C:2]=2[NH:1][C:39]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)=[O:40])=[O:16])[CH2:18][CH2:19]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N)CC2)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3NC(=O)Nc3ccc(F)cc3)CC2)c(C)c1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
[2-Amino-4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (100 mg) described in Example 103 was dissolved in pyridine (2 mL), 4-fluorophenyl isocyanate (64 mg) was added, and the mixture was stirred at room temperature. After completion of the reaction, to the reaction mixture was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (89 mg).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13]C[O:11][CH2:10]1)C1C=CC=CC=1.NCC1(N)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:38])(=[O:39])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13][O:11][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Agent: NCC1(N)COC1
Product: NC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccccc23)COC1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (d, J=1.8 Hz, 1 H), 7.89 (m, J=5.5 Hz, 2 H), 7.63 (m, J=4.0 Hz, 1 H), 7.44 (m, J=7.6 Hz, 3 H), 7.12-7.08 (m, J=4.1 Hz, 1 H), 6.58 (d, J=0.8 Hz, 1 H), 6.22 (s, 1 H), 5.11 (s, 2 H), 4.48-4.39 (m, J=9.0 Hz, 6 H), 3.65-3.58 (m, J=6.1 Hz, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH2:21][CH2:22][OH:23])=[CH:9][C:8]2=[O:24])=[CH:4][CH:3]=1.I[CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:10]([CH2:21][CH2:22][O:23][CH3:28])[CH2:9][C:8]2=[O:24])=[CH:25][CH:26]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH2:21][CH2:22][O:23][CH3:28])=[CH:9][C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CI
Reactant: COc1ccc(-c2cn(Cc3ccc(Cl)cc3)c(=O)cc2CCO)cc1
Product: COCCC1CC(=O)N(Cc2ccc(Cl)cc2)C=C1c1ccc(OC)cc1
Product: COCCc1cc(=O)n(Cc2ccc(Cl)cc2)cc1-c1ccc(OC)cc1
Yield: 171.4 %

Procedure:
According to Scheme 30 Step 4: The title compound was prepared from 1-(4-chlorobenzyl)-4-(2-hydroxyethyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (1 eq, 0.14 mmol, 50 mg) and iodomethane (3 eq, 0.41 mmol, 58 mg) according to the procedure described for Example 34 Step 3. The product was further purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 5 g SiO2) using Et2O/pentane 90/10 to afford 1-(4-chlorobenzyl)-4-(2-methoxyethyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.12 mmol, 47 mg, 91%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2>O1CCCC1.[Pt]>[Cl:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: COC(=O)/C=C/c1c(Cl)cc2nn(C)cc2c1C(=O)OC
Agent: [Pt]
Solvent: C1CCOC1
Product: COC(=O)CCc1c(Cl)cc2nn(C)cc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.4 %

Procedure:
To a solution of methyl 6-chloro-5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-2-methyl-2H-indazole-4-carboxylate (440 mg, 1.43 mmol) in tetrahydrofuran (10 mL) was added 5% platinum-activated carbon (88 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→70/30) to give the title compound (295 mg, yield 66%).
Reaction SMILES: [CH3:1][S:2]([CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1)[CH3:6])(=[NH:4])=[O:3].[C:17](N1C=CN=C1)([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[S:18]>C(#N)C>[CH3:1][S:2](=[O:3])([CH:5]([C:7]1[CH:12]=[N:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][CH:8]=1)[CH3:6])=[N:4][C:17]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[S:18]
Reactant: CC(c1ccc(C(F)(F)F)nc1)S(C)(=N)=O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=NC(=S)n1ccnc1
Temperature: 60 °C

Procedure:
To a solution of 5-[1-(methylsulfonimidoyl)ethyl]-2-(trifluoromethyl)pyridine (E) (400 mg, 1.59 mmol) in acetonitrile (5 mL), 1,1′-thiocarbonyldiimidazole (353 mg, 1.59 mmol, 1 eq) was added and stirred over night. A second aliquot of 1,1′-thiocarbonyldiimidazole (71 mg, 0.317 mmol, 0.2 eq) was added and the mixture heated to 60° C. for two hours. The solvent was removed under reduced pressure, the residue dissolved in CHCl3 and washed five times with water. The organic phase was dried (Na2SO4) and chloroform was removed under reduced pressure. N-(Methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)-1H-imidazole-1-carbothioamide (Y) was obtained as an orange-brown residue, which was dried in the high vacuum over night (371 mg, 1.02 mmol, 64%). A 1:1 mixture of diastereomes with a purity of 94% was observed by UPLC-UV/ELSD and NMR, which was sufficient for subsequent conversions. Higher purities were obtained by filtration of the residue through a plug of silica (7.5% MeOH in CHCl3). 1H NMR (CDCl3, 400 MHz): δ=1.83 (d, J=7.1 Hz, 1.5H, CHCH3, diastereomer 1); 1.86 (d, J=7.1 Hz, 1.5H, CHCH3, diastereomer 2); 2.86 (s, 1.5H, S—CH3, diastereomer 1); 2.89 (s, 1.5H, S—CH3, diastereomer 2); 4.32 (q, J=7.1 Hz, 0.5H, CHCH3, diastereomer 1); 4.37 (q, J=7.1 Hz, 0.5H, CHCH3, diastereomer 2); 7.68-7.85 (m, 2H, Ar), 7.97-8.14 (m, 2H, Ar), 8.67-8.82 (m, 2H, Ar), UPLC-MS (ESI+): mass calc'd for C13H12F3N4OS2 (M+H+): 363.0. Found 363.1, UPLC-MS (ESI−) mass calc'd for C13H14F3N4OS2 (M−H+): 361.0. Found 361.1.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.[NH2:13][C:14]1[C:15]([OH:25])=[C:16]([S:21]([OH:24])(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:27]([NH:13][C:14]1[C:15]([OH:25])=[C:16]([S:21]([OH:24])(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1)=[O:29]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](N)COC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (1 mmol) of (S)-2-(tert-butoxycarbonylamino)-1-propanol (Boc-Ala-ol), 223 mg (1 mmol) of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid and 100 mg (0.33 mmol) of triphosgene were suspended in 3 ml of methylene chloride, and added with 0.7 ml of pyridine. Following agitation at room temperature overnight, the solvent was distilled away, purified using purification step A to obtain a crude purified substance of the title compound in protected form. To the resultant crude purified substance, 2 ml of trifluoroacetic acid was added, and the resultant was stirred at room temperature for 2 hours. Subsequently, the solvent was distilled away, and the resulting residue was added with water and acetonitrile for deposition and the deposited solid was filtrated to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]([OH:33])[CH2:34][N:1]2[CH2:6][CH2:5][CH2:4][C:3]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:2]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCNC1)O2
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCCC3(CSC4=C(O3)c3ccccc3C(=O)C4=O)C2)cc1

Procedure:
Compound 197 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=90-92° C., 400 MHz 1H NMR (CDCl3) δ: 8.04-8.02 (d, J=7.43 Hz, 1H), 7.75-7.73 (d, J=7.82 Hz, 1H), 7.63-7.58 (m, 1H), 7.48-7.44 (m, 1H), 7.31-7.21 (m, 2H), 6.83-6.80 (m, 1H), 4.13-4.07 (m, 1H), 3.15-2.96 (m, 3H), 2.82 (s, 1H), 2.65-2.50 (m, 5H), 2.04-1.73 (m, 4H), 1.29 (s, 9H); LCMS: 508 [M+H].
Reaction SMILES: [CH2:1]([N:4]([CH2:33][CH2:34][CH3:35])[C:5]([C:7]1=[CH:8][C:9]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:22][C:10]=2[N:11]=[C:12]([NH:14]C(=O)OC(C)(C)C)[CH2:13]1)=[O:6])[CH2:2][CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[NH2:14][C:12]1[CH2:13][C:7]([C:5]([N:4]([CH2:33][CH2:34][CH3:35])[CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8][C:9]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:22][C:10]=2[N:11]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(O)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(O)cc3)cc2N=C(N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
tert-Butyl (1E,4E)-4-(dipropylcarbamoyl)-8-(4-hydroxyphenyl)-3H-benzo[b]azepin-2-ylcarbamate (0.040 g, 0.084 mmol) was dissolved in 1 ml of dichloromethane. 0.5 ml of TFA was then added and the mixture was stirred at room temperature for one hour. The reaction was then quenched by the addition of saturated sodium bicarbonate solution and stirred for 15 minutes, then extracted twice with dichloromethane, extracts dried over sodium sulfate and concentrated. Preparative thin layer chromatography (0.5 mm plate, 7% MeOH/DCM) afforded 6 mgs (19%) of (1E,4E)-2-amino-8-(4-hydroxyphenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.47-7.53 (m, 2H), 7.41-7.44 (m, 1H), 7.30-7.33 (m, 1H), 6.88-6.93 (m, 2H), 6.83 (s, 2H), 3.42-3.54 (m, 4H), 2.81 (s, 2H), 1.61-1.72 (m, 4H), 0.89-0.97 (m, 6H); m/z (APCI-pos) M+1=378.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]=2[NH:28][C:29]2[C:30]3[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[N:35][C:31]=3[N:32]=[CH:33][N:34]=2)[CH:5]=[CH:6][C:7]=1[NH:8]C(OCC(Cl)(Cl)Cl)=O.[Li+].[OH-]>C1COCC1>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[NH:28][C:29]2[C:30]3[CH:38]=[CH:37][C:36]([CH:39]([CH3:40])[CH3:41])=[N:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)c(F)c2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(N)c(F)c3)ncnc2n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
The product of Example 449E (1.25 g, 2.0 mmol) in THF (12.5 mL) was reacted with aqueous LiOH solution [prepared from LiOH monohydrate (0.42 g, 10 mmol) and water (8.4 mL)] dropwise at room temperature. The mixture was stirred at 40° C. for 16 hours, and then concentrated. The aqueous mixture was diluted with 50 mL of water, washed with ethyl acetate (1×40 mL), and then carefully acidified to pH 5-6 with 1N HCl under stirring. After 30 minutes, the resulting precipitate was collected by filtration, washed with cold water, and dried at 40° C. for 3 days in vacuum to give the title compound as pale brown crystal (0.77 g, 87%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7. 0 Hz, 6H), 3.23 (septet, J=7.0 Hz, 1H), 5.67 (s, 2H), 7.15-7.30 (m, 2H), 6.81 (dd, J=9.2, 8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 1.8 Hz, 1H), 7.11 (dd, J=11.4, 1.8 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.4, 1.9 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 8.57 (s, 1H), 8.85 (d, J=8.5 Hz, 1H), 10.12 (s, 1H). MS ESI+ m/z: 450 (M+H), ESI− m/z: 448 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH2:24]1[O:26][CH2:25]1.Cl>C(OCC)C.O>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([CH2:24][CH2:25][OH:26])[CH:3]=1
Reactant: C1CO1
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: CCOCC
Product: OCCc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromobiphenyl (18 g, 77 mmol) in diethyl ether (150 ml) under N2 cooled to -78° C. was added 1.6M t-butyl lithium in pentane (100 ml, 0.16 mole) via cannula over a 15 minute period. The solution was stirred 30 minutes at -78° C., ethylene oxide (9 g, 0.2 mole added and the reaction mixture allowed to warm to room temperature over a 1 hour period. The solution was boiled briefly to drive off excess ethylene oxide, transferred to a separatory funnel, a small volume of water added, and neutralized with concentrated HCl. The organic solution was dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:4) to give 2-(3-biphenylyl)ethanol (10.5 g). 1H NMR (CDCl3, 60 MHz) δ: 2.81 (t, J=7 Hz, 2H, CH2), 3.76 (t, J=7 Hz, 2H, CH2), 6.95-7.70 (m, 9H, Ar).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][CH:8]([F:30])[C:9]1[N:20](S(C2C=CC=CC=2)(=O)=O)[C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]2[CH:10]=1.C(OCC)(=O)C>CO.O>[F:30][CH:8]([F:7])[C:9]1[NH:20][C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]2[CH:10]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)cc(C(F)F)n2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]c(C(F)F)cc2c1
Temperature: 40 °C
Yield: 59.6 %

Procedure:
Potassium carbonate (0.25 g, 1.76 mmol) was added to a solution of 2-(difluoromethyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.089 g, 0.252 mmol) in methanol (2.2 mL) and water (0.7 mL). The reaction mixture was heated at 40° C. for 30 minutes. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were separated. The combined organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 2-(difluoromethyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.032 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2COCCOC
Reaction time: 66 h
Yield: 24 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (6 g, 26.5 mmol) in anhydrous DMF (30 ml) was added sodium carbonate (3.09 g, 29.15 mmol). After 10 minutes stirring at room temperature methoxyethoxymethylchloride (3.03 ml, 26.5 mmol) was added and stirring continued under nitrogen at room temperature for 66 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (100 ml) and washed with brine (100 ml), the aqueous extract was extracted with DCM (100 ml) and the organic extracts dried (MgSO4) combined and concentrated in vacuo. The residue was triturated with EtOAc and the solid filtered off. Concentration of the filtrate afforded a light brown oil that was absorbed onto silica and purified by SPE (Si, 50 g) eluting with a gradient of 1:1 EtOAc/cyclohexane-EtOAc to afford the title compound as a white solid (2 g, 24%), m/z 315.2 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[N:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[C:20]([O:31][CH3:32])[CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[N:15]=[CH:14][N:13]([C:18]3[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH:24]([CH:26]4[CH2:27][CH2:28]4)[OH:25])=[C:20]([O:31][CH3:32])[CH:19]=3)[C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Br)ccc1OCC(O)C1CC1
Reactant: O=c1cc(CSc2ccc(Cl)cc2)nc[nH]1
Product: COc1cc(-n2cnc(CSc3ccc(Cl)cc3)cc2=O)ccc1OCC(O)C1CC1

Procedure:
N-arylation of 6-((4-chlorophenylthio)methyl)pyrimidin-4(3H)-one Part B of Procedure 10 with 2-(4-bromo-2-methoxyphenoxy)-1-cyclopropylethanol Part C to generate G-2 was achieved using the procedure described in Part C of Procedure 10. LC/MS 459 (M+H)+, tR 0.97 min (method 5). 1H NMR (400 MHz, Chloroform-D) δ ppm 8.14 (1H, s), 7.26-7.40 (4H, m), 7.03 (1H, d), 6.80-6.91 (2H, m), 6.45 (1H, s), 4.20 (1H, dd, J=9.54, 2.76 Hz), 4.03 (1H, t, J=8.91 Hz), 3.96 (2H, s), 3.87 (3H, s), 3.36 (1H, td, J=8.34, 2.64 Hz), 0.91-1.06 (1H, m), 0.51-0.67 (2H, m), 0.40-0.50 (1H, m), 0.26-0.37 (1H, m).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[F:39][C:40]([F:51])([F:50])[C:41]1[CH:46]=[CH:45][C:44]([N:47]=[C:48]=[O:49])=[CH:43][CH:42]=1.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:6]=[C:5]([CH3:38])[C:4]([NH:3][C:48]([NH:47][C:44]6[CH:43]=[CH:42][C:41]([C:40]([F:39])([F:50])[F:51])=[CH:46][CH:45]=6)=[O:49])=[C:36]([CH3:37])[CH:35]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:32][CH:31]=2)[S:28]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 74.5 %

Procedure:
A mixture of 5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (288 mg), α,α,α-trifluoro-p-tolyl isocyanate (112 mg), triethylamine (121 mg) and anhydrous tetrahydrofuran (10 ml) was stirred at room temperature for 40 hours. The reaction mixture was concentrated and diluted with water. The precipitate was isolated by filtration and washed with water and ethyl acetate to afford the title compound (257 mg, mp 206-208° C.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:5]=1.[Br:26]N1C(=O)CCC1=O.O>O1CCCC1>[Br:26][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(CCCCCc1ccc(Cl)cc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
8.1 g (0.186 mol) of 55% sodium hydride in a mineral oil suspension is added in portions to a solution of 63.4 g (0.186 mol) of ethyl 7-(4-chlorophenyl)-2-ethoxycarbonylheptanoate (BM 13.861) in 500 ml of absolute tetrahydrofuran, and stirred for another 15 minutes to complete the salt formation. Then 33.1 g (0.186 mol) of N-bromosuccinimide is added and the mixture is stirred for 8 h at room temperature. Then it is poured into water, acidified, and extracted with ether. The combined extracts are washed, dried and concentrated by evaporation. The concentrate is chromatograhied with toluene on silica gel. 61.3 g (78% of theory) of ethyl 2-bromo-7-(4-chlorophenyl)-2-ethoxycarbonylheptanoate, a colorless oil, is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([S:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41].[ClH:43]>C(Cl)Cl.C1COCC1>[ClH:36].[ClH:43].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([S:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:13]=2)[CH:16]=1
Reactant: CN(C)CCN
Reactant: Cc1csc(Nc2cc(Sc3cccc(C(=O)O)c3)ccn2)n1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Sc3cccc(C(=O)NCCN(C)C)c3)ccn2)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 42.36 %

Procedure:
A 100 mL round-bottomed flask was charged with 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-ylthio)benzoic acid (0.100 g, 0.2912 mmol) and THF (30 mL) and cooled to −5° C. Triethylamine (0.08840 g, 0.8736 mmol) and ethyl carbonochloridate (0.02784 mL, 0.2912 mmol) were added successively. The reaction mixture was stirred at −5° C. for 30 minutes. N1,N1-dimethylethane-1,2-diamine (0.07701 g, 0.8736 mmol) was added and stirred at −5° C. for 30 minutes and room temperature for 1 hour. An aqueous workup was done, the organic layer was dried and concentrated, and the residue was purified by silica gel chromatography to give the free base. The free base was dissolved in DCM, and 2M HCl was added. The solution was concentrated to provide N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-ylthio)benzamide dihydrochloride (0.060 g, 42.36% yield). 1H NMR (d6-DMSO) δ 11.34 (bs, 1H), 9.97 (bs, 1H), 8.94 (t, 1H), 8.13 (m, 2H), 8.07 (d, 1H), 7.79 (d, 1H), 7.67 (t, 1H), 6.80 (s, 1H), 6.66 (s, 1H), 6.58 (s, 1H), 3.63 (m, 2H), 2.26 (m, 2H), 2.82 (d, 6H), 2.21 (s, 3H); Mass spectrum (apci) m/z=414.0 (M+H-2HCl).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.CCOCC>[C:5]1([C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]=[C:1]=[O:2])[CH2:15][CH2:16]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: N[C@H]1CC[C@H](c2ccccc2)CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C=N[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 80 °C

Procedure:
Phosgene (20% in toluene, 5 ml) was added to a solution of trans-4-phenylcyclohexylamine (500 mg, 2.85 mmol) in toluene (5 ml) under nitrogen at room temperature. The resulting solution was heated at 80° C. for 24 hours. Solvents were then removed under vacuum to leave a solid residue. This residue was dispersed in ether and filtered. The eluent was collected and concentrated to give 379 mg of trans-4-phenylcyclohexylisocyanate as a light yellow oil. IR (film) 2259 cm−1.