Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:22]#[N:23])=[CH:11][S:12][C:13]=1[NH:14][C:15](OC(C)(C)C)=[O:16])=O)(C)(C)C.C(OC(=O)C(OCC)=O)C>C(O)(=O)C>[C:22]([C:10]1[C:9]2[NH:8][C:6](=[O:5])[C:15](=[O:16])[NH:14][C:13]=2[S:12][CH:11]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1scc(C#N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Product: N#Cc1csc2[nH]c(=O)c(=O)[nH]c12

Procedure:
A mixture of 4-bis(t-butoxycarbonyl)amino-5-t-butoxycarbonylamino-3-thiophene carbonitrile (15.4 g, 35 mmol), diethyloxalate (100 ml, 739 mmol) and glacial acetic acid (100 ml) was refluxed for 6 h. The crystallinic product was filtered off and washed with ether to give 3.25 9 (48%) of the title compound. M.p.>250° C. 1H-NMR (DMSO-d6, δ): 8.15 (s, 1H), 12.4 (br.s, 1H), 12.5 (br.s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:14][N:13]([C:15](=[O:17])[CH3:16])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:26]>>[ClH:26].[CH2:12]1[C:10]2([CH2:11][NH:8][CH2:9]2)[CH2:14][N:13]1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)N1CC2(C1)CN(C(=O)OC(C)(C)C)C2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CC2(CNC2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 6-Acetyl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (131) (300 mg, 1.33 mmol) in CH2Cl2 (10 mL) were added TFA (388 mg, 4.0 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with CH2Cl2 (20 mL), washed with H2O (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered, evaporated to give the product (132) (176 mg, 1.0 mmol, yield: 75%). ESI-MS (M+1): 141 calc. for C7H12N2O 140.
Reaction SMILES: Cl.ClC1C=C(NN)C=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:23]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:20]2)[CH:15]=[CH:16][C:17]=1F>>[Cl:31][C:26]1[CH:25]=[C:24]([C:23]2[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=3)[N:20]=[C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:22]=2)[CH:29]=[C:28]([F:30])[CH:27]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: NNc1cccc(Cl)c1
Product: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 1A and 3-chlorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 5.82 g of the title compound are obtained.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:12]12.[OH-].[Na+]>C(O)(=O)C>[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]1[C:19]([CH2:3][N:4]([CH3:1])[CH3:5])=[C:18]([CH3:20])[N:17]=[C:12]12
Reactant: Cc1cn2ccc3c(Cl)cccc3c2n1
Reactant: CNC
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CN(C)C
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 71.2 %

Procedure:
To a solution of 37% aqueous formaldehyde (0.42 g) and 50% aqueous dimethylamine (0.46 g) in acetic acid (3.2 ml) was added 7-chloro-2-methylimidazo[2,1-a]isoquinoline (1 g) and the mixture was warmed at 50° C. with stirring for 3.5 hours. The solution was poured into ice water and neutralized with an aqueous solution of sodium hydroxide. The resulting precipitates were collected by filtration, washed with water and recrystallized from a mixture of toluene and n-hexane to give 7-chloro-3-dimethylaminomethyl-2-methylimidazo[2,1-a]isoquinoline (0.9 g).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:15]([O:22][NH:23][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: NOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=CNc1nc(Cl)c(NC=O)c(NOCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamido-pyrimidine (1.9 g, 8.09 mmol), benzyloxyamine (1 g, 8.13 mmol), triethylamine (2 ml) and dioxan (20 ml) was stirred at 100° C. for 1 hour. The cooled reaction mixture was filtered and the precipitate collected and washed with dioxan (2×5 ml). The filtrate and washings were combined and evaporated to a syrup. Column chromatography on silica gel (eluted with chloroform-ethanol, 30:1) afforded the title compound (1.2 g, 46%). IR: νmax (KBr) 3242, 1694, 1588, 1472 cm-1 ; 1H NMR δH [(CD3)2SO], 4.89 (2H, s, OCH2Ph), 7.4 (5H, m, Ph), 8.15 (1H, s, CHO), 9.18, 9.42 (1H, 2×br.s, D2O exchangeable, NH), 9.25 (1H, br.s, CHO), 10.91 (2H, br.s, D2O exchangeable, 2×NH). m/z (FAB+ve ion, thioglycerol) MH+ 322.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5].[H]1[BH2][H][BH2]1>>[ClH:1].[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Product: Cl
Product: NCc1c([N+](=O)[O-])ccc(Cl)c1Cl

Procedure:
As shown below in the Examples, a preferred process is set forth for making 2-amino-5,6-dichloro-3,4-dihydroquinazoline from commercially available starting materials. In one process 1,2,3-trichlorobenzene is used as the starting material and is nitrated using, for example, nitric/sulfuric acids to form 1,2,3-trichloro-4-nitrobenzene. This compound is then reacted with a cyanating agent such as CuCN to form 2,3-dichloro-6-nitrobenzonitrile. The nitrile is then reacted under reducing conditions using for example B2H6 to form 2,3-dichloro-6-nitrobenzylamine HCl which is then reduced and reacted with CNX to form the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=1.O.[CH3:25][N:26](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:25]#[N:26])[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: O=Cc1cc(-c2ccccc2Br)n(S(=O)(=O)c2cccnc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccccc1-c1cc(C=O)cn1S(=O)(=O)c1cccnc1
Yield: 63 %

Procedure:
A suspension of 5-(2-bromophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (102 mg), zinc cyanide (61.0 mg) and tetrakis(triphenylphosphine)palladium (60.0 mg) in N,N-dimethylformamide (2 mL) was heated (100 W, 4 min 30 sec) using a microwave focused chemical synthesis reactor manufactured by CEM, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 97.4 mg, 63%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[C:8](Cl)(=[O:10])N.CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][NH2:29])=[N:26][CH:27]=1>C(Cl)Cl>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]([C:8]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[O:10])[NH2:29])=[N:26][CH:27]=1
Reactant: NNc1ccc(F)cn1
Reactant: NC(=O)Cl
Reactant: C[C@H]1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1C(=O)N(N)c1ccc(F)cn1
Temperature: 45 °C
Yield: 57.3 %

Procedure:
Pyridine (1.60 mL, 19.8 mmol) was added dropwise to an ice cold suspension of triphosgene (2.94 g, 9.90 mmol) in DCM (20.0 mL). (S)-3-Methylmorpholine (1.00 mL, 9.90 mmol) was added and the reaction stirred for 3 hours, then quenched by dropwise addition of HCl (1M aqueous, 20 mL). The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give (S)-3-methylmorpholine-carbamoylchloride (1.25 g, 77%). The product was used in the next reaction without purification. (S)-3-Methylmorpholine-carbamoylchloride (766 mg, 4.33 mmol) was dissolved in DCM (35.0 mL) and DIPEA (1.03 mL, 5390 mmol) was added followed by (5-fluoro-pyridin-2-yl)-hydrazine (WO2010022076, 500 mg, 3.94 mmol) and the reaction heated to 45° C. overnight. The reaction was cooled and quenched into water. The mixture was extracted into DCM (3 x). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3in MeOH] in DCM to give the title compound (574 mg, 57%). 1H NMR (300 MHz, CDCl3): 1.36 (3H, d, J=6.9 Hz), 3.30 (1H, td, J=12.5, 3.9 Hz), 3.47-3.74 (4H, m), 3.89-4.03 (2H, m), 6.41 (1H, br s), 6.45 (1H, br s), 6.73 (1H, dd, J=9.0, 3.5 Hz), 7.29 (1H, ddd, J=9.0, 7.9, 2.9 Hz), 8.04 (1H, d, J=2.9 Hz).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH:7]1[N:15]([CH2:16][CH2:17][CH3:18])[C:1](=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCCNC1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C(=O)CC)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
Propionic acid chloride (2 mL, 2.1 g, 23 mmol) was added dropwise to a solution of indan-2-yl-propylamine (4.0 g, 23 mmol) and triethyl amine in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours. Aqueous (10%) sodium carbonate was added and the mixture was shaken. The organic phase was dried (magnesium sulfate), filtered and evaporated to yield 4.5 g (85%) of the title compound as an oil.:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]2[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:17]=[N:18][C:14]=2[CH:13]=[C:12]([Cl:30])[N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:17]1[N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[C:15]2[C:10]([Cl:9])=[N:11][C:12]([Cl:30])=[CH:13][C:14]=2[N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(Cn2c(Br)nc3cc(Cl)nc(Cl)c32)cc1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (352 mg, 1.98 mmol) was added to a solution of 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (200 mg, 0.99 mmol) stirring in degassed chloroform (20 mL) at room temperature. The reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 2-bromo-4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. MS APCl calc'd. for C14H7BrCl2F3N3 [M+H]+ 426. found 426.
Reaction SMILES: [S:1]1CC(=O)[NH:3][C:2]1=[O:7].[H-].[Na+].[Li+].[CH3:11]C([N-]C(C)C)C.CI.C1[CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:11][O:7][C:2]1[S:1][CH:21]=[C:22]([O:23][CH3:24])[N:3]=1
Reactant: C1CCOC1
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)[N-]C(C)C
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CI
Product: COc1csc(OC)n1

Procedure:
To a stirred solution of 2,4-thiazolidindione (0.01 mol) in a solvent such as THF is added from 2 to 4 mol equivalents of a non-nucleophilic base such as sodium hydride or LDA, followed by methyl iodide, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 2,4-dimethoxythiazole, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][SnH:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.CC(C)=O>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Sn:18]([CH3:20])([CH3:19])[CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[SnH](C)C
Reactant: C=CCCCCS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)CCCCCC[Sn](C)(C)C)cc1

Procedure:
The procedure described in Example 1 was employed except that 10.1 g (42.5 mmole) of 5-hexenyl p-tolyl sulfone and 14.0 g (85 mmoles) of trimethyltin hydride were the reactants. The reaction mixture was irradiated for 232 hours. The excess trimethyltin hydride was allowed to evaporate from the reaction mixture under a flow of nitrogen. The unreacted 5-hexenyl p-tolyl sulfone was removed from the reaction mixture by distillation at I × 10-3 mm Hg leaving 3.25 g of crude product. Column chromatography of the distillation residue over silica gel, employing toluene and 1% acetone in toluene as eluents, afforded an oil, 6-(p-tolylsulfonyl)hexyltrimethylstannane. The presence of both the sulfonyl and trimethyltin moieties was indicated by the strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1285 cm-1 and 1140 cm-1 (--SO2 --) and 760 cm-1 [(CH3)3Sn-]. NMR showed the following:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH:26]=[CH2:27])[CH:3]=1.C([O-])(=O)C.[Na+].O>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:24][CH:25]=1)[C:6](=[O:7])[N:8]([CH2:9][C:10]1[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=1)[CH:27]=[CH:26]2
Reactant: C=Cc1cc(Cl)ccc1C(=O)NCc1ccnc2cc(OC)c(OC)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Cn3ccc4cc(Cl)ccc4c3=O)c2cc1OC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-Chloro-N-((6,7-dimethoxyquinolin-4-yl)methyl)-2-vinylbenzamide (0.084 g, 0.22 mmol), sodium acetate (0.036 g, 0.44 mmol), and palladium acetate (0.002 g, 0.011 mmol) were combined in DMSO (5 ml). The reaction mixture was stirred under an oxygen balloon at 100° C. overnight. The mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by prep-TLC plate with ethyl acetate to give 6-chloro-2-((6,7-dimethoxyquinolin-4-yl)methyl)isoquinolin-1(2H)-one. MS (ESI, pos. ion) m/z: 381 (M+1). 1H NMR (CDCl3): 4.03 (6H, s), 4.80 (1H, d), 5.95 (1H, d), 5.40 (2H, s), 7.05 (1H, d), 7.40 (1H, s), 7.56 (2H, m), 7.70 (1H, s), 7.87 (1H, d), 8.64 (1H, d).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@@H:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][OH:31]>>[OH:31][CH2:30][C@@H:29]([NH:28][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:24])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)[C@H](N)CO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@H](CO)C(C)C)cc2)CC1
Yield: 80 %

Procedure:
By the same procedure as described in the example 30, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using (S)-(+)-2-amino-3-methyl-1-butanol. Then, the product was recrystallized using ethanol and isopropyl ether to give a desired compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.O[CH:14]1[CH2:19]SC(O)C[S:15]1.C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:15][CH:14]=[CH:19][C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1sccc1C(=O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 116.6 %

Procedure:
A mixture of 4-fluorobenzoylacetonitrile (2.84 g), 2,5-dihydroxy-1,4-dithian (1.31 g), triethylamine (2.2 ml) and ethanol (15 ml) was stirred for 40 minutes at 50° C. The reaction mixture was cooled to give 2-amino-3-(4-fluorobenzoyl)thiophene as yellow crystals (2.22 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17](B5OC(C)(C)C(C)(C)O5)[CH:16]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1.Br[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([C:31]5[CH:35]=[CH:34][S:33][C:32]=5[C:36]#[N:37])[CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1
Reactant: N#Cc1sccc1Br
Reactant: CC1(C)OB(c2cccc(-n3cnc4cc(-c5ccoc5)cnc43)c2)OC1(C)C
Product: N#Cc1sccc1-c1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1

Procedure:
The title compound was prepared from 6-(furan-3-yl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3H-imidazo[4,5-b]pyridine and 3-bromothiophene-2-carbonitrile as described in Example 8 to afford the free base as a tan sold; δH (400 MHz, d6-DMSO) 7.17 (1H, s), 7.70 (1H, d, J 5), 7.78-7.86 (3H, m), 8.15 (1H, d, J 8), 8.20 (1H, d, J 5), 8.36-8.37 (2H, m), 8.50 (1H, d, J 2), 8.78 (1H, d, J 2), 9.02 (1H, s); m/z (ES+) 369 (M++H).
Reaction SMILES: Br[C:2]1[C:3]([S:8][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].Cl>O1CCCC1.CCCCCC>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]([C:2]1[C:3]([S:8][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1)[OH:19]
Reactant: CSc1ncncc1Br
Reactant: O=Cc1ccccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ncncc1C(O)c1ccccc1F
Temperature: -25 °C
Yield: 39.7 %

Procedure:
To a slurry of 20 g (98 mmol) of 5-bromo-4-methylthiopyrimidine in 200 mL of anhydrous tetrahydrofuran at -90° C. was slowly added with stirring and cooling 40 mL (100 mmol) of 2.5M n-butyl lithium in hexane. After a 20-min reaction period, 13.3 g of 2-fluorobenzaldehyde was added with stirring. The solution was allowed to gradually warm to -25° C. It was then poured into dilute aqueous hydrochloric acid with stirring. The resulting mixture was extracted with ether and the ethereal extract was dried over magnesium sulfate, filtered, and partially concentrated by evaporation under reduced pressure. The remaining mixture was diluted with hexane and the solids that formed were collected by filtration to obtain 9.75 g of the title compound as colorless solid melting at 176°-177° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[Li]CCCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>C1COCC1>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a cooled (-78° C.), stirred solution of 2-bromo-5-(tert-butyldimethylsiloxy)methylpyridine (6.8 g, 0.022 mol) in THF (60 mL) was added 1.6M nBuLi in hexanes (14.1 mL, 0.022 mol). After 1 h, tri-n-butyltin chloride (6.1 mL, 0.022 mol) was added and stirring was continued for 3 h. Water was added, and the mixture was warmed to room temperature and extracted with ether. The combined extracts were dried (MgSO4) and concentrated to give 11.5 g (100%) of product as a brown oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:28])[CH3:27])[CH:20]=4)[C@@H:14]([CH3:29])[CH2:13]3)[N:11]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[C:10](=[O:37])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:38][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.C(O)(=O)C>C1COCC1>[CH:1]1([N:7]=[C:8]2[C@:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:27])[CH3:28])[CH:20]=4)[C@@H:14]([CH3:29])[CH2:13]3)[N:11]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[C:10](=[O:37])[N:9]2[CH3:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Oc1cccc(CN2CC[C@@]3(C[C@@H]2C)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)Oc1cccc(CN2CC[C@@]3(C[C@@H]2C)C(=NC2CCCCC2)N(C)C(=O)N3c2cccc(F)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (11-10, 0.5 g, 0.1 mmoles) was dissolved in THF (2 mL) in an oven-dried flask and the solution was cooled under nitrogen to −78° C. in a dry ice/acetone bath. To the cooled reaction was added a 1 M solution of Lithium bis(trimethylsilyl)amide in THF (0.3 mL, 0.3 mmoles) dropwise, and the solution was warmed to −20° C. for 10 min. The solution was cooled to −50° C. and iodomethane (0.014 g, 0.1 mmole) was added and the reaction stirred for 30 min at −50° C. The reaction was then allowed to warm to rt. A drop of acetic acid was added and the volume was reduced. The residue was partitioned between saturated aqueous sodium bicarbonate (5 mL) and methylene chloride (5 mL). The organic layer was dried over sodium sulfate, filtered and reduced to a residue which was chromatographed on silica gel eluting with a gradient elution of 100% methylene chloride going to 30% methylene chloride/methanol/10% NH4OH solution over 20 min. The desired fractions were combined and the solvents removed to give the product.