Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@H]1CCCC[C@H]1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound, colorless oil, MS: m/e=568.1 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and N-tert-butoxycarbonyl-4-piperidone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:21])=O.C[O-].[Na+]>CN(C)C=O.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[NH2:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)C1CCN(Cc2ccccc2)CC1

Procedure:
To a mixture of 1-benzyl-4-ethoxycarbonylpiperidine (6.88 g) and formamide (3.71 ml) in N,N-dimethylformamide (30 ml) was added 28% sodium methoxide solution in methanol (4.0 ml) at 100° C. under stirring. After stirring at 100° C. for 1 hour, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine and dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ether to give 1-benzyl-4-carbamoylpiperidine (2.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:13]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[CH:3]=[C:4]([S:13]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(N2CCCC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(S(=O)(=O)Nc2ccsc2C(=O)O)ccc1N1CCCC1
Temperature: 80 °C
Yield: 58.3 %

Procedure:
To a solution of 122 (85.0 mg; 0.22 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added aqueous sodium hydroxide (7.5 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether. The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×15 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with dichloromethane/methanol to give the title product as an off-white solid (47 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:13](=[O:15])[C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:12]=3)[S:61][C:51]=2[C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[N:53][CH:54]=1
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-(4-morpholinyl)-4-pyridinecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 448 (M+H+, 100).
Reaction SMILES: [C:1]12([C:11]3[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:20])([CH3:21])[C:17]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:18])=[CH:22][CH:23]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)(Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)C(=O)O
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)C(C)(C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 94.1 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoic acid (0.2 g, 0.63 mmol), prepared from the step 2 of example 23, and N,N-dimethylethane-1,2-diamine (0.056 g, 0.63 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)-2-methylpropanamide as a white solid (0.228 g, 93.4% yield).
Reaction SMILES: C([N:8]1[CH2:22][CH:21]([CH3:23])[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][CH:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CCOC(C)=O>[CH3:23][C@H:21]1[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9][NH:8][CH2:22]1
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CC2Cc3ccccc3C(=O)N12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1CNC[C@H]2Cc3ccccc3C(=O)N21
Reaction time: 72 h
Yield: 27.7 %

Procedure:
1,2,3,4,11,11a-Hexahydro-2-benzyl-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (from Isomer B, 93 mg, 0.30 mmol) and 10% palladium on carbon (40 mg) in EtOAc (9 ml) was stirred under a balloon of hydrogen. After 3 days the reaction was about 60% complete by HPLC. The catalyst was filtered off and then fresh catalyst added. After stirring an additional day under a balloon of hydrogen, the reaction was filtered through Celite® rinsing with EtOAc and methanol to afford 56 mg of crude product. Column purification (Chiralcel OD, 15% 1/1 MeOH/EtOH in hexanes) afforded pure (4R,11aR)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (18 mg, 28% yield). MS (ESI) 217 (M+H). Further elution afforded pure (4S,11aS)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (16 mg, 25% yield). MS (ESI) 217 (M+H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16])C1C=CC=CC=1.[H][H]>C1COCC1.CCO.[Pd]>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[N:12][C:11]=1[CH2:10][CH2:9][OH:8]
Reactant: [H][H]
Reactant: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCO
Yield: 60.2 %

Procedure:
A solution of {4-[4-(2-benzyloxy-ethyl)-5-methyl-oxazol-2-yl]-phenyl}-methyl-phenyl-amine (195 mg, 0.490 mmol) in THF (2 mL) and EtOH (10 mL) was treated a slurry of Pd/C (200 mg) in EtOH (2 mL). The resulting mixture was treated with hydrogen under balloon pressure for 14 h and filtered through a pad of Celite. The filtrate was concentrated, and crude product was purified by silica gel chromatography column (50% EtOAc/hexanes) to yield the title compound (91 mg, 60%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[CH2:45][CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([C:18]1[N:17]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:16]=[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=1[C:34]([N:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (33 mg, 0.054 mmol) in DCM (2.0 mL) was added TFA (1.0 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was used directly in the next step without further purification. MS(ESI+) m/z 552.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Br)c(C)o1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of methyl 5-methyl-2-furancarboxylate (2.33 g, 16.29 mmol) and aluminum chloride (3.3 g, 24.75 mmol) in chloroform (50 ml) at room temperature was added Br2 (1.1 ml, 21.35 mmol). The resulting solution was stirred at room temperature in a 150 mL sealed tube reactor for 2 hours. Upon completion, the solution was cooled in an ice bath, H2O added and reaction partitioned between CHCl3/H2O. The organic layer was washed with NaHCO3 and then Na2S2O3. The organic layer was dried with Na2SO4, concentrated, adsorbed onto silica and purified via column chromatography (0-20% EtOAc/Hexanes) affording the title compound (2.13 g, 9.72 mmol, 60%): LC-MS (ES) m/z=221 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14]>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([S:11][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[S:9][CH:10]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)Cc1csc(S)n1
Product: CCOC(=O)Cc1csc(SCC(=O)OC(C)(C)C)n1

Procedure:
The title compound was obtained by an operation similar to that of Example 2 and using (2-mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester synthesized in Example 1 and bromoacetic acid tert-butyl ester to give {2-[(2-tert-butoxy-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid ethyl ester, followed by sequential operations similar to those of Examples 3, 4 and 100.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br-].[K+].C(N(CC)CC)C.Cl>CN1CCCC1=O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)CNCc1ccccc1
Yield: 94 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine, 1 g of potassium bromide and 5.2 g (51 mmol) of triethylamine are heated in 20.6 g of N-methylpyrrolidone in an autoclave at an internal temperature of 120° C. for 6 hours. Subsequently, 100 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 30 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 7.4 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 94%, based on benzylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)[CH:12]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2cccnc2)ccn1
Temperature: 150 °C
Yield: 93 %

Procedure:
4-Chloro-2-pyridine carbonitrile (1.0 g, 7.2 mmol, 1.0 eq), 3-hydroxypyridine (686 mg, 7.21 mmol, 1.00 eq) and K2CO3 (1.2 g, 8.7 mmol, 1.2 eq) were dissolved in DMF (10 mL) and heated in a microwave for 15 minutes at 150° C. The reaction was cooled, diluted with EtOAc and washed with H2O (3×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 1.32 g (93%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=5.8 Hz, 1H), 8.56 (m, 2H), 7.79 (d, J=2.4 Hz, 1H), 7.75 (dt, J=8.4, 1.4 Hz, 1H), 7.55 (dd, J=8.3, 4.7 Hz, 1H), 7.27 (dd, J=5.7, 2.4 Hz, 1H); ES-MS [M+1]+: 198.0.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1ccc(N=C=S)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
Into a solution of 2-chloro-4fluoroaniline (500 mg, 3.44 mmol) in a mixture of chloroform and water (10 mL/10 mL) at room temperature, thiophosgene (0.53 mL, 6.88 mmol) and sodium bicarbonate (1.09 g, 10.32 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between chloroform and water. The combined organic layer was then concentrated to give the desired product (586 mg, 91%). 1H NMR (CDCl3) δ 6.98 (m, 1H), 7.20 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][C@H:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[NH+]1C=C[CH:27]=[CH:26][CH:25]=1.COC(OC)(C)C>C(Cl)(Cl)Cl>[CH2:8]([C@@H:7]1[O:11][C:26]([CH3:27])([CH3:25])[N:12]([C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[C@H:6]1[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[C:21]([F:23])[CH:20]=1)[CH:9]=[CH2:10]
Reactant: c1cc[nH+]cc1
Reactant: C=CC[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Solvent: COC(C)(C)OC
Solvent: ClC(Cl)Cl
Product: C=CC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Alcohol (32) was stirred in chloroform with pyridinium p-toulenesulfonate and 2,2-dimethoxypropane to afford (33) as an amber oil after workup.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27]C)=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([OH:27])=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Temperature: 90 °C

Procedure:
To a solution of (methyl (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)-carboxylate), 5-(4-morpholinylcarbonyl) (25 mg, 0.05 mmol) in MeOH//THF (1:1, 1.6 mL) was added 1 M aqueous NaOH (0.80 mL). The reaction mixture was stirred and heated at 90° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (1 mL), neutralized with 1M aqueous HCl (0.80 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carboxylic acid, 5-(4-morpholinylcarbonyl) (21 mg, 0.05 mmol, 85%) as a light yellow solid. 1HNMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.63 (dd, J=8.4, 1.5 Hz, 1H), 7.60-7.47 (m, 3H), 7.29 (dd, J=7.0, 1.5 Hz, 1H), 4.84 (br s, 2H), 3.98-3.55 (m, 4H), 3.23-3.05 (m, 2H), 2.88-2.69 (m, 5H), 2.12-1.63 (m, 6H), 1.51-1.06 (m, 4H). LCMS: m/e 472 (M−H)−, ret time 1.39 min, column A, 3 minute gradient.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:18][CH:19]=3)[CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>CO.O>[CH3:26][N:24]([CH3:25])[S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][N:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:12]=3)[CH2:14]2)=[CH:19][CH:18]=1)(=[O:28])=[O:27]
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCc3ccc(S(=O)(=O)N(C)C)cc3C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](O)c1nccc(N2CCc3ccc(S(=O)(=O)N(C)C)cc3C2)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 31 %

Procedure:
To a solution of (R)-1-[4-(7-dimethylsulfamoyl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 247, Step C, 326 mg, 0.81 mmol) in a 4:1 mixture of methanol/water (8 mL) was added lithium hydroxide hydrate (170 mg, 4.0 mmol). This mixture was stirred at room temperature for 50 min, concentrated, re-suspended in water, and extracted with 10% isopropanol/chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give a white foam which was further purified by recrystallization from ether/methanol to give 90 mg (31%) of the title compound as a white solid. mp: 120.5-122° C.; 1H NMR (CDCl3, 300 MHz) δ 8.24 (d, 1H), 7.62-7.59 (c, 2H), 7.35 (d, 1H), 6.44 (d, 1H), 4.83 (s, 2H), 4.73 (q, 1H), 4.34 (br s, 1H), 3.93-3.85 (c, 2H), 3.03 (t, 2H), 2.71 (s, 6H), 1.52 (d, 3H); MS (TS) 363 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4].C1C(=O)N([Br:34])C(=O)C1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Br:34])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc(CNC=O)nc1Nc1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a −30° C. solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (1.84 g, 4.89 mmol) in dichloromethane (50 mL) under N2 was added NBS (0.96 g, 5.38 mmol, 1.1 eq.), and the reaction mixture was stirred at −30° C. for 3 h. More NBS (0.96 g, 5.38 mmol, 1.1 eq.) was added, and the reaction mixture was allowed to stand at 0° C. for 18 h. The reaction mixture was diluted with ethyl acetate (250 mL). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was triturated with methanol to afford the desired product as a yellow solid (1.50 g, 80.1%). LCMS (method C): RT=2.51 min, [M+H]+=383/384.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[SH:11][CH2:12][CH2:13][OH:14].[H-].[Na+]>>[CH3:9][C:4]1[C:3]([CH3:10])=[C:2]([S:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][N+:5]=1[O-:8]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Product: Cc1c(SCCO)cc[n+]([O-])c1C

Procedure:
According to the procedure indicated in Example A2. a), reaction of 4-chloro-2,3-dimethylpyridine-N-oxide with 2-mercaptoethanol and sodium hydride gives the title compound as an oily residue, which is employed in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Br:23]Br>C(Cl)(Cl)Cl.O>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[C:10]([Br:23])=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: COc1c(F)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1c(F)cnc2c1c(Br)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of 5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 68b, (0.79 g, 2.45 mmol) in chloroform (50 mL) was added bromine (0.13 mL, 2.45 mmol). The reaction mixture was stirred at 0° C. for 3 hours and then slowly warmed to ambient temperature. The mixture was diluted with deionized water and quenched with aqueous sodium bicarbonate. The aqueous phase was extracted with methylene chloride and dried over sodium sulfate. The resulting solid was purified via silica gel chromatography (15-30% EtOAc/Hexanes) to give 170 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1csc(-c2ccc(Cl)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1csc(-c2ccc(Cl)cc2)n1
Yield: 25 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 25%). 1H NMR (400 MHz, CDCl3) δ 8.53 (m, 1H), 8.27-8.25 (m, 1H), 8.10-8.05 (m, 2H), 7.86-7.84 (d, J=8.5 Hz, 2H), 7.62-7.59 (t, J=7.8 Hz, 1H), 7.33-7.31 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 3.71-3.69 (d, J=5.3 Hz, 2H), 1.49 (s, 6H). MS (ESI) m/z: Calculated for C23H18ClF3N4O2S: 506.08. found: 507.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]5)=[C:18]([O:28][CH3:29])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@@H:24]([O:27][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:23]5)=[C:18]([O:28][CH3:29])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-6-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one (2.407 g, 5.34 mmol) in CH2Cl2 (50 mL) and add MsCl (0.46 mL, 5.87 mmol) and Et3N (1.0 mL, 7.32 mmol). Stir the mixture at RT for one hour. Dilute the mixture with CH2Cl2 (50 mL) and wash with water (30 mL). Dry the solution with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 10% EtOAc/CH2Cl2 to give 1.05 g (37%) of the title compound. LC-MS/ES m/z (35Cl) 531.8 [M+H]+.