Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[N:10]([CH2:26][C:27](=[O:36])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[Li+].[BH4-].O>C1COCC1>[CH:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:14]([C:11]2[N:10]([CH2:26][C:27](=[O:36])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:3][OH:2])[C:13]=3[N:12]=2)=[O:25])[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(CO)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
85.0 mg (0.166 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 3 mL abs. THF. Under argon 0.25 mL (0.497 mmol) of a 2 M LiBH4-solution in THF were added. After stirring for 1.5 h at room temperature 0.5 mL water were added and the reaction mixture was concentrated. The residue was purified by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-hydroxymethyl-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as a white amorphous solid. The title compound was obtained as its formiate. Yield: 20 mg MS (ES+): m/e=485, chloro pattern.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:32]=1)[C:20](=[O:29])[CH2:21]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH2:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][N:19]([C:20](=[O:29])[CH3:21])[CH2:18][CH2:17][CH2:16][N:6]2[C:5](=[O:42])[NH:4][C:3]3[C:7]2=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=3[NH2:1])[CH:32]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CC(=O)OC(C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(C)=O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from example 20 step (i) (100 mg) was dissolved in DCM (1 ml) and TFA (0.2 ml) added. The mixture was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO3 and dried. The mixture was purified by RPHPLC, which afforded the title compound. Yield 30 mg
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][S:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:33])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: COC(=O)CSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)CS(=O)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Methyl ({[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl}thio)acetate (0.10 g, 0.28 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.064 g, 0.28 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.096 g, 92%) as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].O.NN>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:27][CH:28]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Compound (f) of Example 6 (3.85 g, 0.01 mole) is dissolved in 100 mL of absolute ethanol with warming. Hydrazine hydrate (7.5 mL) is added at once. The solution is heated to reflux for 10 minutes and the reaction mixture sets up. The mixture is cooled to room temperature and filtered. The precipitate is washed with excess hot ethanol. The ethanol fraction is rotovapped to a pale yellow oil. Chromatography on silica gel using methylene chloride/25% methanol as the mobile phase yields 1.6 g (66%) of a pale yellow oil. 1H NMR (CDCl3) 7.83 (1H, d, J=7 Hz); 7.6-7.2 (7H, m); 3.92 (2H, s); 3.66 (3H, s); 2.16 (2H, bs). Mass Spec. (DCl) m/z 242 (M+H). Analysis--calc'd for C15H15NO2.H2O: C, 71.97; H, 6.44; N, 5.60; found: C, 71.60; H, 6.27; N, 5.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[NH4+].C(OCC)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(=O)O)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CCCO)cc1OC
Reaction time: 8 h

Procedure:
A solution of 6.0 g (28.5 mmol) 3-(3,4-dimethoxyphenyl)-propionic acid in 120 ml anhydrous THF is cooled to 0° C. and treated within 15 minutes with 42.75 ml borane THF complex (1 M solution). Stirring is continued overnight at rt. The resulting clear solution is cooled with an ice/water bath and hydrolyzed by the addition of 100 ml saturated ammonium chloride solution. Extractive work-up with diethyl ether furnishes a colourless oil, which is purified by chromatography (hexane/ethyl acetate) to yield a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][CH2:16][O:15][C:4]1[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=[CH:2][N:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Reactant: NCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(C)(C)OC(=O)c1ccnc(OCNCc2ccccc2)c1

Procedure:
t-Butyl 2-chloro-6-methoxypyridine-4-carboxylate (1.0 g) (D60) was heated in benzylamine (20 mL) for 16.5 h at 140° C. After cooling, the mixture was poured into citric acid solution (10% aq.) and extracted twice with ether. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to a yellow gum. This was chromatographed on silica, eluting with hexane/ether, giving the title compound (D54) as an off-white solid (0.411 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12]O)=[CH:4][CH:3]=1.O1CCCC1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH2:12][C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnoc1-c1ccc(Cl)s1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: ClCc1cnoc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a mixture of 5-(5-chloro-2-thienyl)-4-isoxazolylmethanol (6.54 g), tetrahydrofuran (20 ml) and toluene (100 ml) was added dropwise thionyl chloride (5.41 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals of 4-chloromethyl-5-(5-chloro-2-thienyl)isoxazole (6.98 g, yield 98%) were obtained from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio) and recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 70–71° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16](C3C=CN=CC=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[S:44](Cl)(=[O:46])=[O:45]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:44]([C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)(=[O:46])=[O:45])[N:17]=[C:16]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:9][N:8]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccccn2)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 100 mg 5isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with thiophene-2-sulfonylchloride to give 85 mg 5-isopropyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.78 min, [M+1]+=683.61, [M−1]−=681.70.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:30]2[CH:26]([CH2:27][NH:28][CH2:29]2)[C:25](=[O:31])[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:30]2[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:1])[CH3:13])[CH2:29]2)[C:25](=[O:31])[CH2:24][CH2:23]1
Reactant: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CNCC12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3F)(c3ccccc3F)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
N,N'-Carbonyldiimidazole (0.44 g) is added to a solution, cooled to +4° C., of (2-dimethylaminophenyl)acetic acid (0.49 g) in dry dichloromethane (20 cc). The mixture is stirred for 1 hour at 25° C. and a solution of 7,7-bis(2-fluorophenyl)perhydro-4-isoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 20 hours at 25° C. and washed with water (2×100 cc) and with saturated sodium chloride solution (100 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50:50) and collecting 10-cc fractions. Fractions 14 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis(2 -fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (1 g), the hydrochloride of which is prepared by dissolution in ethyl acetate (2 cc) and the addition of a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(2-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone hydrochloride (0.87 g) is obtained in the form of a white solid.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@:19]2([CH3:52])[C:23](=[O:24])[N:22]([CH2:25][C:26]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:27])[C:21](=[O:40])[N:20]2[CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[CH:15][CH:14]=1)#[N:12]>C(O)C>[NH2:12][C:11](=[N:3][OH:2])[C:13]1[CH:18]=[CH:17][C:16]([C@@:19]2([CH3:52])[C:23](=[O:24])[N:22]([CH2:25][C:26]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:27])[C:21](=[O:40])[N:20]2[CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[CH:15][CH:14]=1
Reactant: [NH3+]O
Reactant: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccc3ccccc3c2)C(=O)N1Cc1ccc2ccccc2c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@]1(c2ccc(C(N)=NO)cc2)C(=O)N(CC(=O)OCc2ccc3ccccc3c2)C(=O)N1Cc1ccc2ccccc2c1
Yield: 86.4 %

Procedure:
1.67 g (24 mmol) of hydroxylammonium chloride and 5.04 ml (36 mmol) of triethylamine were added to a solution of 6.64 g (12 mmol) of 2-naphthylmethyl ((S)-4-(4-cyanophenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate in 120 ml of absolute ethanol and the mixture was heated under reflux for 2.5 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The phases were separated and the water phase was extracted with ethyl acetate. The combined organic phases were washed with water and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo and 6.08 g (86%) of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cc1cccnc1Oc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: CS(C)=O
Product: Cc1cccnc1Oc1ccc(C[C@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)cc1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-methyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][C:33]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:46]4[CH2:47][CH2:48][N:43]([C:41]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=[C:33]([CH3:32])[CH:42]=5)[CH2:44][CH2:45]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Product: Cc1cc(N2CCN(C(=O)c3ccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)cc3)CC2)c2ccccc2n1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-methyl-4-(1-piperazinyl)quinoline as in General Procedure 10 to give the title compound. LCMS: m/z=656.96 (M+H+); retention time=0.62 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH2:25][SH:26])[CH:22]=[CH:23][CH:24]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][S:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 167, Step 1, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and (3-trifluoromethyl-phenyl)-methanethiol.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:21][CH:22]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOCc1ccc(CC(Cl)=NO)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOCc1ccc(Cc2cc(-c3ccc(N)nc3N)on2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.3 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (14.6 mg, 0.11 mmol) described in Manufacturing Example 13-1-3 and 4-butoxymethyl-phenyl-acetohydroximoyl chloride (28 mg, 0.11 mmol) described in Manufacturing Example 4-1-4 in tetrahydrofuran was added triethylamine (31 μL, 0.22 mmol), which was stirred for 4 hours at room temperature. The reaction solution was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) and then purified again by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (6.7 mg, 13%) as a trifluoroacetic acid salt.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=C(O)Cc1ccccc1CBr
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1CBr

Procedure:
A solution of 0.18 g. of o-bromomethylphenylacetic acid in excess thionyl chloride is stirred at room temperature for 18 hours after which the unreacted thionyl chloride is removed under high vacuum to give o-bromomethylphenylacetyl chloride as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:28][C@H:27]([CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C=O)C.O>[N:41]([CH2:29][C@@H:27]1[CH2:28][C@H:25]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)[N:9]=2)[CH2:26]1)=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn43)C2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cis-toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl ester (100 mg, 0.18 mmol) in DMF (2 mL) was charged with sodium azide (35 mg, 0.54 mmol), the resulting mixture was stirred at rt overnight. The mixture was diluted with water (5 mL), then extracted with ethyl acetate (3×10 mL), the combined organic phases were washed with water (2×10 mL) and brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with 100% ethyl acetate), yielding the title compound as a white solid; LC-MS (ES, Pos.): m/z 426 [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.36-2.44 (m, 2H), 2.63-2.79 (m, 3H), 3.37 (d, J=6.7 Hz, 2H), 3.69 (m, 1H), 5.14 (s, 4H, —OCH2— and —NH2), 7.02-7.05 (m, 2H), 7.10 (d, J=5.0 Hz, 1H), 7.25-7.45 (m, 8H).
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][C:6]=1[F:31])([OH:4])=[O:3].[CH:32]([C:34]1[N:35]=[C:36]([NH:39][C:40](=[O:42])[CH3:41])[S:37][CH:38]=1)=O.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:40]([NH:39][C:36]1[S:37][CH:38]=[C:34]([CH:32]=[CH:9][C:8]2[CH:29]=[CH:30][C:5]([C:2]([OH:4])=[O:3])=[C:6]([F:31])[CH:7]=2)[N:35]=1)(=[O:42])[CH3:41]
Reactant: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reactant: CC(=O)Nc1nc(C=O)cs1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of (4-carboxy-3-fluorobenzyl)(triphenyl)phosphoniumbromide (2.037 g, 4.112 mmol) and N-(4-formyl-1,3-thiazol-2-yl)acetamide (599.5 mg, 3.523 mmol) in anhydrous N,N-dimethylformamide (15 ml) was added potassium tert-butoxide (1.180 g, 10.52 mmol), and the mixture was stirred at room temperature for 3 hr. Water (150 ml) was added to the reaction mixture, and the mixture was washed 3 times with ethyl acetate. While stirring, 1M hydrochloric acid (10.5 ml) was added to the aqueous layer. The precipitated solid was collected by filtration and washed with water. The solid was dried under reduced pressure to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}-2-fluorobenzoic acid (753.9 mg, 2.461 mmol, yield 69.9%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@H:12]2[O:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C1COCC1.[Pd].NCCN>[NH2:1][C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@H:12]2[O:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Agent: [Pd]
Solvent: NCCN
Solvent: C1CCOC1
Product: Nc1cccc(OC[C@@H]2CO2)c1

Procedure:
Compound 16a-S (0.5 g, 2.6 mmol) and % 5 Pd/C(en) (10% of the weight of starting material) in 5 ml anhydrous THF was hydrogenated at ambient pressure and temperature for 3-5 hours. The reaction mixture was filtered by using a membrane filter (13, 0.22 μm), and the filtrate was concentrated in vacuo. The resulting compound is a crude mixture of nitro group reduction and epoxide ring opening. Isolation of the desired compound was difficult because of the lability of the components of the mixture on silica gel. The product ratio of the NO2 reduction and ring opening (80:20) was determined on the basis of the integration ratio of the epoxide-ring protons from nitro group reduction and the methyl proton of the ring opened compound (98% total yield for the mixture).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2>>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([NH:11][C:2]3[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccc2ncccc2c1
Product: O=C(O)c1cccnc1Nc1ccc2ncccc2c1
Temperature: 140 °C

Procedure:
A mixture of 2-chloronicotinic acid (1.5 g) and 6-aminoquinoline (1.4 g) was heated at 140° C. neat for 2 h. The reaction was cooled to give a brown solid used in the next step without further purification. MS (ES+): 266 (M+H)+; (ES−): 264 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH:8]=2)[N:3]=1.O=S(Cl)[Cl:27]>C(Cl)Cl>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([Cl:27])=[O:20])[CH:8]=2)[N:3]=1
Reactant: CCCN1Cc2cc(Oc3cccc(C(=O)O)c3)ccc2N=C1N
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCN1Cc2cc(Oc3cccc(C(=O)Cl)c3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoic acid (0.0009 mol) in SOCl2 (2 mL) and DCM (10 mL) was stirred for 2 hours at room temperature and then the solvent was evaporated. The obtained residue was stirred in toluene and the solvent was evaporated again to yield the title compound as a residue.