Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].N1CCCCC1.[CH:14]1([NH:17][C:18]2[N:23]3[N:24]=[CH:25][C:26]([CH:27]=O)=[C:22]3[N:21]=[C:20]([NH:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=3)[CH:19]=2)[CH2:16][CH2:15]1>C(O)C.O>[CH:14]1([NH:17][C:18]2[N:23]3[N:24]=[CH:25][C:26](/[CH:27]=[C:7]4/[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]/4)=[C:22]3[N:21]=[C:20]([NH:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=3)[CH:19]=2)[CH2:15][CH2:16]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Nc3cc(F)cc(F)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Nc4cc(F)cc(F)c4)nc23)N1
Temperature: 80 °C
Reaction time: 12 h
Yield: 27.3 %

Procedure:
Hydantoin (28 mg, 0.28 mmol) and piperidine (42 μL, 0.42 mmol) were added to 7-(cyclopropylamino)-5-(3,5-difluorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (52 mg, 0.16 mmol) dissolved in ethanol (1 mL). The reaction was heated at 80° C. After 12 h, the reaction was cooled to r.t., diluted with water (2 mL), and the precipitate was collected and washed with 1:1 ethanol:water (5 mL). The solid was dried in vacuo to give (Z)-5-((7-(cyclopropylamino)-5-(3,5-difluorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (18 mg, 28% over 3 steps). LCMS (M+1=440)
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=2)=[O:18])=[C:12]([C:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=2)[CH:11]=1)[CH2:6][N:7]=[N+]=[N-])=[N+]=[N-].O.CO.[NH4+].[Cl-]>C1COCC1.[Zn]>[NH2:7][CH2:6][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=2)=[O:18])=[C:12]([C:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=2)[CH:11]=1)[CH2:4][NH2:1]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN=[N+]=[N-])CN=[N+]=[N-])cc1C1=CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN)CN)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-azido-1-azidomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared above, 546 mg, 1.00 mmol) was dissolved in THF (1 mL), water (2 mL) and MeOH (10 mL). To this solution NH4Cl (534 mg, 25.0 mmol) and Zn powder (653 mg, 10.0 mmol) were added with cooling. The resulting mixture was stirred at RT for 30 min and filtered through a thin pad of Celite. The filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated, dissolved in 5% i-PrOH/DCM and washed with satd aq NaHCO3 (20 mL). The organic layer was dried (Na2SO4) and concentrated to obtain the title compound (207 mg, 42%): Mass spectrum (ESI, m/z): Calcd. for C26H38N6O2Si, 495.3 (M+H), found 495.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:19]=[C:20]1[NH:24][C:23](=[O:25])[CH:22]([CH2:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)[S:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH:17][C:33](=[O:34])[CH2:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH:22]2[S:21][C:20](=[O:19])[NH:24][C:23]2=[O:25])=[CH:37][CH:36]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(NC(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(N(C)C(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a suspension at 0° C. of N-(2-amino-5-methoxyphenyl)-N-methylcarbamic acid t-butyl ester (4.2 g) and 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (5.2 g) in methylene chloride (30 ml) was added triethylamine (5.1 ml) and 50% propylphosphonic acid cyclic anhydride in ethyl acetate (12.7 g) and the mixture was stirred at the same temperature for 2 hours. At the end of this time to the reaction mixture was added 5% aqueous sodium hydrogencarbonate solution and the mixture was extracted with methylene chloride. The extract was washed with water and diluted hydrochloric acid and concentrated in vacuo. To the residue was added methanol (40 ml) and the precipitated crystals were filtered to give the title compound (7.3 g, yield 85%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH3:11].[H-].C([Al+]CC(C)C)C(C)C.CC(O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:11][S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccccc1SC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CSc1ccccc1CO
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 83.9 %

Procedure:
To a solution of 2-methylsulfanylbenzoic acid methyl ester (0.30 g, 1.7 mmol) in toluene (3.0 mL), diisobutylaluminum hydride (0.94 mol/L toluene solution, 3.9 mL, 3.7 mmol) was added dropwise at −78° C. and the solution was stirred for 3.5 hours. The reaction mixture was added with 2-propanol (0.20 mL), warmed to 0° C., and added with saturated aqueous potassium sodium tartrate solution to separate the mixture into organic layer and aqueous layer. The obtained organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate=90/10 to 70/30) to obtain (2-methylsulfanylphenyl)methanol (0.22 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)[CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([N+:34]([O-:36])=[O:35])=[C:21]([CH:23](C(OCC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:22]=2)=[N:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Cl-].[Li+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)[CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([N+:34]([O-:36])=[O:35])=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:22]=2)=[N:14][N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(CC[C@H](Cc3ccc(C(F)(F)F)nc3)NC(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(-c2nnc(CC[C@H](Cc3ccc(C(F)(F)F)nc3)NC(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 79.3 %

Procedure:
A mixture of diethyl 2-(5-(5-((R)-3-(tert-butoxycarbonylamino)-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)malonate (165 mg, 242 μmol), water (4 μL, 242 μmol), and lithium chloride (51 mg, 1210 μmol) in DMSO (2 mL) was heated at 100° C. for 24 hours. The mixture was cooled to room temperature and partitioned between saturated aqueous NH4Cl (15 mL) and DCM (15 mL). The layers were separated, and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 40% to 70% EtOAc/hexanes) to provide ethyl 2-(5-(5-((R)-3-(tert-butoxycarbonylamino)-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)acetate (117 mg, 79%) as a white solid. LCMS (API-ES) m/z: 610.0 (M+H+).
Reaction SMILES: [N:1]1(C(OC(Cl)C)=O)[CH2:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1>CO>[NH:1]1[CH2:2][CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)Cl)CC1
Solvent: CO
Product: CCOC(=O)C1=CCNCC1
Temperature: 25 °C

Procedure:
1-(1-Chloroethyl) 4-ethyl 3,6-dihydro-1,4(2H)-pyridinedicarboxylate (61.8 g, 236 mmol) in methanol (500 mL) was heated at reflux for 30 minutes. The mixture was allowed to cool to room temperature and concentrated to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 6.86 (m, 1H), 4.22 (q, 2H), 3.85 (m, 2H), 3.34 (m, 2H), 2.75 (m, 2H), 1.30 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2.OS(O)(=O)=O.[N+:28]([O-])([O-:30])=[O:29].[K+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:28]([O-:30])=[O:29])[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:20])([F:21])[F:22])[CH2:6][CH2:5]2
Reactant: O=C1c2ccc(F)cc2CCN1c1cnccc1C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1c2cc([N+](=O)[O-])c(F)cc2CCN1c1cnccc1C(F)(F)F
Yield: 80.2 %

Procedure:
6-Fluoro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (78A: 600 mg, 1.93 mmol) was reacted with concentrated H2SO4 (5 mL) and KNO3 (215.2 mg, 2.12 mmol) for 4 hours to afford 550 mg of the product (79.9% yield).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=1)[C:15]([NH:17][CH3:18])=[O:16].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)C#N.[NH4+].[Cl-]>O1CCCC1>[Br:9][C:10]1[CH:19]=[C:14]2[C:13]([CH:20]=[C:18]([C:28]3[CH:27]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:29]=3)[NH:17][C:15]2=[O:16])=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: CNC(=O)c1cc(Br)ccc1C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2cccc(Cl)c2)cc2ccc(Br)cc12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 20.5 %

Procedure:
To a solution of 2M lithium diisopropylamide (19.73 mL, 39.5 mmol) in tetrahydrofuran (30 mL) at −78° C. was added dropwise a solution of 5-bromo-N,2-dimethylbenzamide (Intermediate 22A) (3.0 g, 13.15 mmol) in THF (14 mL) followed by a solution of 3-chlorobenzonitrile (1.809 g, 13.15 mmol) in THF (14 mL) and the mixture was stirred at −78° C. for 2.5 hours. Reaction allowed to warm to room temperature and saturated NH4Cl (aq) was added. The THF was removed under reduced pressure and the resulting mixture extracted into ethyl acetate and washed with brine (precipitate was observed in both layers). Organics were evaporated to dryness, washed with methanol and dried in a vacuum oven to afford 7-bromo-3-(3-chlorophenyl)isoquinolin-1(2H)-one (0.9 g, 2.69 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[Cl:23][CH2:24][C:25](Cl)=O>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][N:10]1[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=[C:25]1[CH2:24][Cl:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21
Yield: 72 %

Procedure:
Using the general method of Examples 43-68 Part A, tert-butyl[2-(3-aminoquinolin-4-ylamino)ethyl]carbamate (43.5 g, 144 mmol) was reacted with chloroacetyl chloride (17.72 g, 158 mmol) to provide 37.39 g of tert-butyl[2-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate.
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:37][C:36]=1[Cl:51])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[ClH:51].[ClH:1].[Cl:51][C:36]1[CH:37]=[C:38]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:45][CH:46]=2)[CH:39]=[CH:40][C:35]=1[CH2:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
557 ml of a 4 N solution of hydrogen chloride in dioxane, diluted with a further 389 ml of dioxane, were added to 79 g (111.39 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 74A), and the mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the residue was dried under high vacuum overnight. This gave 78 g (111.39 mmol, about 100% of theory) of the target product.
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([NH:16][C:17](=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][N:13]([CH3:15])[CH3:14])C1C=CC=CC=1.CN(C)C[C@H](NC(=O)CCCCCCCCN(C)CCC1C=CC=CC=1)CC(O)=O>>[CH3:15][N:13]([CH3:14])[CH2:12][C@H:11]([NH:16][C:17](=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][C:9]([OH:35])=[O:8]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCN(C)c1ccccc1
Agent: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCCCCCCN(C)CCc1ccccc1
Product: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCCCCCCN(C)c1ccccc1

Procedure:
Hydrogenation of (R)-4-dimethylamino-3-[9-(methyl-phenyl-amino)-nonanoylamino]-butyric acid benzyl ester in analogy with example 1, step 4 produced (R)-4-dimethylamino-3-[9-(methyl-phenethyl-amino)-nonanoylamino]-butyric acid. White solid, m/e=392.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[CH:16]=[C:15]([NH:17][S:18]([C:21]2[S:22][C:23](Br)=[CH:24][CH:25]=2)(=[O:20])=[O:19])[O:14][N:13]=1>>[CH3:11][C:12]1[CH:16]=[C:15]([NH:17][S:18]([C:21]2[S:22][C:23]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=3)=[CH:24][CH:25]=2)(=[O:20])=[O:19])[O:14][N:13]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)s2)on1
Reactant: Nc1cccc(B(O)O)c1
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3cccc(N)c3)s2)on1

Procedure:
N-(3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32C from 3-amino benzene boronic acid (256 mg, 1.87 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (55 mg, 1.7 mmol). Purification by column chromatography using 15% MeOH/CHCl3 gave 318 mg (56%) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)(=O)C>>[OH:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: CC(=O)Oc1cccc(C=O)c1
Product: COC(=S)c1cc(NCc2cccc(O)c2)c(C)s1

Procedure:
Using the procedure described in Example 220, step (a), 1.6 mg (0.30 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 49.5 mg (0.30 mmol) of 3-acetoxybenzaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAC)3 were allowed to react to give methyl 4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C14H16NO3S2, 352.07 (M+H), found, 350. 2 (imine), 352.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]([C:25]([O:27]C)=O)=[CH:23][N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:29][NH2:30]>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]([C:25]([NH:30][CH3:29])=[O:27])=[CH:23][N:24]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1cnc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)s1
Solvent: CO
Product: CNC(=O)c1cnc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)s1
Temperature: 39 °C

Procedure:
In a flask was placed methyl 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)thiazole-5-carboxylate (80.8 mg, 0.2 mmol) and MeOH (4 mL) was added. Then, 40 wt % CH3NH2(aq) (6 mL) was added and the resulting mixture was heated to 38-40° C. for 4 h. The resulting mixture was concentrated to remove MeOH and then partitioned in CH2Cl2/H2O (30 mL/30 mL). The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator and the resulting residue re-solidified from CH2Cl2/hexane to yield 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)-N-methylthiazole-5-carboxamide as a white solid.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][C:4]([CH2:7]Cl)=[CH:3][CH:2]=1.[Cl:11][CH2:12][CH2:13][OH:14]>>[Cl:11][CH2:12][CH2:13][O:14][CH2:9][C:1]1[CH:2]=[CH:3][C:4]([CH2:7][O:14][CH2:13][CH2:12][Cl:11])=[CH:5][CH:6]=1
Reactant: OCCCl
Reactant: ClCc1ccc(CCl)cc1
Product: ClCCOCc1ccc(COCCCl)cc1

Procedure:
To 5.0 g of p-xylylene dichloride was added 25 ml of 2-chloroethanol, and the mixture was refluxed for 24 hours. After the reaction, 2-chloroethanol was removed under reduce pressure at 100° C. The residue was applied to a silica gel column and eluted with hexane/chloroform (1:1) as eluent, and a relevant fraction was further purified by distillation to obtain 2.44 g of the title compound as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[CH:26][CH:27]=[CH:28][C:15]3=4)[C:11](=[O:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH:25]1[C:16]2[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]([C:12]3[C:11](=[O:29])[NH:10][C:9](=[O:30])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])[N:7]=4)[CH:13]=3)[C:15]=2[CH:28]=[CH:27][CH:26]=1
Reactant: O=c1[nH]c(=O)n(-c2ccnc(Cl)n2)cc1C1c2ccccc2C=Cc2ccccc21
Reactant: COC(=O)CN
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNc1nccc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Temperature: 90 °C

Procedure:
A mixture of the product from example 6 step (i) (1 g), glycine methyl ester hydrochloride (0.339 g) and N,N-diisopropylethylamine (1.13 ml) in 1-methyl-2-pyrrolidinone (20 ml) was heated at 90° C. for 7 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in methanol/chloroform and the product precipitated by the addition of 50% ethyl acetate in isohexane. Yield 0.96 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]#[N:8])[NH:5][CH:6]=1.[OH-].[Na+].[I:11]I>ClCCl>[I:11][C:6]1[NH:5][C:4]([C:7]#[N:8])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1c[nH]c(C#N)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc(C#N)[nH]c1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
Into a 25-mL round bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 4-methyl-1H-imidazole-2-carbonitrile (compound 14.2, 350 mg, 3.27 mmol) and aqueous sodium hydroxide (2 M, 5 mL) and stirred for 15 min at room temperature. This was followed by the drop-wise addition of a solution of iodine (1.25 g, 4.92 mmol) in dichloromethane (5 mL). The resulting mixture was stirred for 24 h at room temperature, then diluted with water/ice (10 mL). The aqueous layer was washed with DCM (10 mL), and then the aqueous layer was acidified to pH 5-6 with acetic acid. The aqueous phase was extracted with EtOAc (5×50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 500 mg (66%) of the title compound as a brown solid.
Reaction SMILES: S(C)C.[Li+].[Cl-].[CH3:6][Mg]Cl.[CH3:9]/[C:10](=[CH:31]\[CH2:32][CH2:33][CH3:34])/[C:11]([N:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:15][C:14]1=[O:30])=[O:12]>C1COCC1.[NH4+].[OH-].[NH4+].[Cl-].O.C(O)(=O)C>[CH3:9][C@H:10]([C@H:31]([CH3:6])[CH2:32][CH2:33][CH3:34])[C:11]([N:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:15][C:14]1=[O:30])=[O:12]
Reactant: CCC/C=C(\C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCC[C@@H](C)[C@@H](C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 22 L 4-neck round bottom flask was equipped with an addition funnel, mechanical stirrer, and nitrogen inlet. The system was purged with nitrogen for 1 hour. THF (6 L) were charged to the flask followed by 1236 g (6.01 mol) of CuBr.S(CH3)2 and 364 g (8.59 mol) of LiCl. The reaction was stirred for 15 minutes at ambient temperature. The solution was cooled to −35° C. and 3.96 L (11.88 mol) of a 3M solution of CH3MgCl in THF was charged at a rate as to keep the internal temperature of the reaction mixture below −25° C. The reaction was stirred for 1 hour after the addition of CH3MgCl was complete. (4S,5R)-3-((E)-2-Methyl-hex-2-enoyl)-4,5-diphenyl-oxazolidin-2-one (1.00 Kg, 2.86 mol) was added as a solid in one portion and the reaction was stirred at −30° C. for 4 hours. The reaction mixture was transferred over a 2 hour period into another 22 L flask equipped with a mechanical stirrer, transfer line, vacuum line, and containing 4 L of 1:1 acetic acid:THF solution cooled in an ice-water bath. The quenched solution was stirred for 30 minutes and then diluted with 4 L of 2M NH4OH in saturated aqueous NH4Cl and 2 L of water. The biphasic mixture was stirred for 15 minutes and the phases separated. The organic phase was washed 4× with 4 L aliquots of the 2M NH4OH solution. No more blue color was observed in the washes or the organic phase so the organic phase was diluted with 8 L of water and the THF was distilled off until the internal temperature of the distillation pot reached 95° C. The suspension was cooled to ambient temperature and filtered. The solids were washed with 4 L of water and suction dried to give 868.2 g of an off white solid. This material was recrystallized from 2 L of 95:5 heptane:toluene with a cooling rate of 5° C. per hour to provide 317.25 g of the titled compound as a white solid: 1H NMR (CDCl3) 7.12-6.85 (m, 10H), 5.90 (d, 1H, J=8.06 Hz), 5.72 (d, 1H, J=7.81), 3.83-3.76 (m, 1H), 1.95-1.89 (m, 1H), 1.35-1.31 (m, 1H), 1.11 (d, 3H, J=6.84), 1.10-0.95 (m, 3H), 0.92 (d, 3H, J=6.59), 0.76 (t, 3H, J=7.20) MS (APCI) M+1=366.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:15])[N:9]3[CH2:22][CH2:23][N:24]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][CH:28]1[O:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[N:9]3[CH2:22][CH2:23][N:24]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][CH:28]1[O:33][CH2:32][CH2:31][NH:30][CH2:29]1
Reactant: COc1c(OCCC2CN(C(=O)OC(C)(C)C)CCO2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OCCC2CNCCO2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
tert-Butyl 2-[2-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)ethyl]morpholine-4-carboxylate (650 mg, 1.44 mmol) was dissolved in trifluoroacetic acid (10 mL) and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure, and the resulting oil was diluted with methanol (1 mL) and pulled through a silica bound-NH2 cartridge. The solution was concentrated under reduced pressure to give the title compound as a solid (45 mg, 69%): HPLC MS RT=0.21 min, MH+=451.1; 1H NMR (DMSO-d6) δ: 12.8-12.7 (1H, br s), 9.32 (1H, s), 8.73 (1H, d), 8.46 (1H, d), 7.60 (1H, d), 7.54-7.49 (1H, m), 7.06 (1H, d) 4.22-3.99 (6H, m), 3.94 (3H, s), 3.78 (1H, d), 3.66-3.58 (1H, m), 3.47 (1H, t), 2.95 (1H, d), 2.82-2.65 (2H, m), 1.98-1.78 (2H, m).