Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:23])/[CH:14]=[C:15]2\[O:16][C:17]([CH3:22])([CH3:21])[O:18][C:19]\2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:25]1C=C(/C=C/CCN)C=CC=1Cl>>[Cl:8][C:7]1[CH:6]=[C:5](/[CH:4]=[CH:9]/[CH2:10][CH2:11][NH:12][C:13](=[O:23])/[CH:14]=[C:15]2\[O:16][C:17]([CH3:21])([CH3:22])[O:18][C:19]\2=[O:20])[CH:25]=[CH:3][C:2]=1[Cl:1]
Reactant: NCC/C=C/c1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)NCCCc2ccc(Cl)c(Cl)c2)O1
Product: CC1(C)OC(=O)/C(=C/C(=O)NCC/C=C/c2ccc(Cl)c(Cl)c2)O1
Yield: 54 %

Procedure:
By appropriate application of method used to synthesize Intermediate 5, Intermediate 6 (41 mg, 0.19 mmol) was converted to Example 143 A (38 mg, 0.10 mmol, 54% yield). HPLC/MS (Method D) RT=1.06 min, [M+H]+ 370.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[O:64]1[C:68]([C:69](O)=[O:70])=[CH:67][CH:66]=[N:65]1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][N:51]([C:69]([C:68]5[O:64][N:65]=[CH:66][CH:67]=5)=[O:70])[CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccno1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)c2ccno2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.3 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and isoxazole-5-carboxylic acid (0.110 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine as a white solid (0.045 g). 1H NMR Spectrum: (DMSO d6 373K) 1.86 (m, 2H), 2.10 (m, 2H), 3.59 (m, 2H), 3.88 (m, 2H), 3.98 (s, 3H), 4.92 (m, 1H), 6.87 (s, 1H), 7.26 (m, 1H), 7.38 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 8.62 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 498.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].[C:17]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2ncc(C(=O)O)c(Br)c2n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2ccc(OC)nc2c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
To a solution of 4-bromo-6-(methoxy)-[1,5]naphthyridine-3-carboxylic acid (for a synthesis see WO2004058144, Example 53(d)) (8.28 g, 29.3 mmol) in DMF (200 ml) was added K2CO3 (5.934 g, 43 mmol) and iodomethane (2.18 ml, 35 mmol) and the reaction was stirred at rt for 72 h. The reaction was partitioned between EtOAc and water. The organic phase was separated and washed twice more with water. The aqueous phases were re-extracted with EtOAc and this EtOAc phase separated and washed with water. The combined organic phases were dried and evaporated to give the desired product as a solid (7 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][S:14][C:15](SC)=[C:16]([C:21]#[N:22])[C:17]([O:19][CH3:20])=[O:18]>C1COCC1.CCCCCC>[C:21]([C:16](=[C:15]([S:14][CH3:13])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]([O:19][CH3:20])=[O:18])#[N:22]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: Nc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C#N)=C(Nc1cccnc1)SC
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
1.39 g (14.8 mmol) of 3-aminopyridine are dissolved in 50 ml of THF, cooled to −20° C., and 7.4 ml of a 2M solution of n-butyllithium in hexane are added. After stirring for 15 min, 2.00 g (9.84 mmol) of methyl 3,3-bis(methylthio)-2-cyanoacrylate are added. The mixture is warmed to room temperature while stirring and then hydrolyzed with ice-water. The product is extracted with dichloromethane. After drying over sodium sulfate, the solvent is removed in vacuo and the residue is purified by preparative HPLC. 0.44 g (18.1% of theory) of the desired product is obtained.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C@H:18]([CH3:21])[CH2:19][OH:20]>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C[C@H](CO)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CO)Cn1c2ccccc2c2ccccc21
Temperature: 45 °C
Reaction time: 48 h
Yield: 22.3 %

Procedure:
Carbazole (0.50 g, 3.0 mmol) was dissolved in dry DMF (20 mL) and NaH (60% dispersion in oil) (0.36 g, 9.0 mmol) was added. The resulting mixture was stirred under a N2 atmosphere at 25° C. for 30 min. (R)-(-)-3-Bromo-2-methyl-1-propanol (1.14 g, 7.5 mmol) was added in 4 portions over a period of 10 min, and the mixture stirred at 45° C. for 48 h. The solvent was removed in vacuo. Addition of water (20 mL), extraction with CH2Cl2 (3×20 ml), drying of the organic phases (MgSO4) and evaporation of the solvent in vacuo gave an oil that was purified on a silica gel column (Eluent: ethyl acetate/n-heptane (1:1)). This afforded the title compound 0.16 g (23%) as a white solid. M.p. 80-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=3[CH3:30])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=3[CH3:30])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)Nc2cc(-c3cccc(Cl)c3)ccc2C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc(Cl)c3)ccc2C(=O)O)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(3-chlorophenyl)-2-(2,3-dimethylbenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 32 mg of 4-(3-chlorophenyl)-2-(2,3-dimethylbenzamido)benzoic acid as white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO.Cl>O>[OH:7][CH:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C/C(O)c1nc2ccc(F)cc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCC/C=C/C(O)C1=Nc2ccc(F)cc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
A solution of 715 mg (5.18 mmols) of potassium carbonate in 3 ml of water was added to a solution of 1.86 g (5.18 mmols) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-4-acetoxy-6-fluoroquinoline, 50 ml of methanol and 2 ml of water and stirred at room temperature for 10 minutes. After neutralization by addition of 1N hydrochloric acid, the solvent was distilled off under reduced pressure and 30 ml of chloroform was added to the resultant residue, followed by washing with water and drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (solvent: chloroform : methanol=40:1) to obtain 1.19 g (yield 72 %) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-6-fluoro-4-quinolone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][C:20]#[CH:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][C:20]#[CH:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: C#CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 71.7 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propynyl)-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is treated in the same manner as described in Example 2. 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propynyl)-3-D-galactopyranosylurea are thereby obtained as a pale yellow powder.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C@@H:10](O)CC)=[S:7])(C)(C)[CH3:2]>Cl>[CH2:1]([NH:5][C:6]1[S:7][CH2:10][CH:9]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:8]=1)[CH3:2]
Reactant: CC[C@H](O)[C@@H](Cc1ccncc1)NC(=S)NC(C)(C)C
Agent: Cl
Product: CCNC1=NC(Cc2ccncc2)CS1
Temperature: 100 °C

Procedure:
A suspension of 4.2 g of N-tert-butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea in 40 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 100° C. for 20 hours. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is chromatographed at atmospheric pressure on a column of silica gel (particle size 40-63μ; diameter 3.6 cm; height 24 cm), eluting with a dichloromethane/methanol mixture (98/2 by volume) and then with a dichloro-methane/methanol mixture (97/3 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions, taken up in 30 cm3 of dichloromethane and basified with 1N sodium hydroxide. The organic phase is dried over magnesium sulfate, filtered and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. 1.4 g of (+)-(4R,5R)-5-(ethyl-4-(4-pyridylmethyl)-4,5-dihydro-2-thiazolylamine are obtained in the form of a white solid melting at 124° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.83 (t, J=7.5 Hz: 3H); 1.43 (mt: 1H); 1.61 (mt: 1H); 2.70 (limiting AB: 2H); 3.40 (mt: 1H); 4.08 (mt: 1H); 6.28 (unresolved complex: 2H); 7.29 (broad d, J=5.5 Hz: 2H); 8.45 (broad d, J=5.5 Hz: 2H), (αD20=+166.9+/−2.4 at a concentration of 0.5% in methanol)].
Reaction SMILES: [C:1]1([C:7](=[N:16][NH2:17])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:20][C:21](=O)[CH2:22][N+:23]([O-:25])=[O:24])C.N1CCCCC1>C1C=CC=CC=1>[N+:23]([C:22]1[C:21](=[O:20])[NH:17][N:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:25])=[O:24]
Reactant: NN=C(C(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=c1[nH]nc(-c2ccccc2)c(-c2ccccc2)c1[N+](=O)[O-]

Procedure:
8.96 g (0.040 mole) of benzilmonohydrazone, 5.3 g (0.040 mole) of ethylnitroacetate and 4.8 g (0.056 mole) of piperidine in 100 mL of benzene were heated in a round bottom flask with a Dean-Stark trap and condenser for 24 hrs.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([C:8](=[O:14])[CH:9](C)[C:10](O)=O)=[N:6][CH:7]=1.C(O)(=O)C.[Cl:20]Cl>O>[Cl:20][CH:9]([CH3:10])[C:8]([C:5]1[C:4]([F:15])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:14]
Reactant: ClCl
Reactant: CC(C(=O)O)C(=O)c1ncc(Cl)cc1F
Solvent: CC(=O)O
Solvent: O
Product: CC(Cl)C(=O)c1ncc(Cl)cc1F
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
20.8 g of 3-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3-oxopropionic acid (Example P35) are introduced into 125 ml of glacial acetic acid. 6.3 g of chlorine gas are introduced into the solution in the course of 1 hour . The mixture is then poured into 700 ml of water and extracted with tert-butyl methyl ether. The combined ethereal phases a rewashed with water and dried over magnesium sulfate, filtered and concentrated by evaporation in vacuo. The crude product is dissolved in 180 ml of tert-butyl methyl ether, 45 g of silica gel are added and the mixture is stirred for 30 minutes, in the course of which the evolution of gas observed initially comes to a halt. The silica gel is then filtered off and subsequently washed and the combined ethereal phases are concentrated to dryness in vacuo. 20.1 g of an oily crude product are obtained, which is purified over a flash chromatography column (silica gel; eluant: n-hexane/ethyl acetate 411 (v/v)). 17.0 g of the desired title compound are obtained in the form of a solid having a melting point of 29-32° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1>>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: O=C(Nc1ccccc1)c1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]-N-phenylbenzamide was prepared from 2-amino-N-phenylbenzamide and 2,4,5-trichloropyrimidine using a procedure substantially as described for the preparation of Intermediate 1. Mass (M+H)+=358, 360.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[N:12]1[CH:17]=[CH:16]C=[CH:14][CH:13]=1.O1CCCC1.C(NCC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([N:12]([CH2:17][CH3:16])[CH2:13][CH3:14])=[O:8]
Reactant: O=C(Cl)c1cc(Cl)ccc1I
Reactant: c1ccncc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
In a 100 mL round bottomed flask was placed the 5-chloro-2-iodobenzoyl chloride prepared above. Pyridine (50 mL, 600 mmol) and tetrahydrofuran (10 mL, 100 mmol) were then added. To the reaction mixture was added diethylamine (3 mL, 30 mmol) and the mixture was stirred for 3 hr at rt. The mixture was stirred for an additional 3 hr at 50° C. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and then washed with 1N HCl (50 mL×2), 1N NaOH (50 mL), brine (50 mL), and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (1.96 g, 61%) as a light yellow syrup. LCMS: (FA) ES+ 338, 340; 1H NMR (300 MHz, d6-DMSO) δ ppm 7.86 (d, 1H), 7.38 (d, 1H), 7.21 (dd, 1H), 3.61-3.68 (m, 1H), 2.91-3.29 (m, 3H), 1.17 (t, 3H), 1.01 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](O)=[O:30]>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][N:27]([CH3:32])[CH3:26])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CN(C)CC(=O)O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Product: CN(C)CC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 56 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (206 mg, 0.57 mmol) and N,N-dimethylglycine (65 mg, 0.63 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([C:25]4([CH3:30])OCC[O:26]4)=[CH:21][C:20]=3[O:31]COC)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:16]2[C:11]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:35])=[C:20]([OH:31])[CH:21]=1)(=[O:26])[CH3:30]
Reactant: COCOc1cc(C2(C)OCCO2)ccc1C(=O)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Yield: 18.6 %

Procedure:
N-(5-Chloropyridin-2-yl)-3-[4-(2-methyl-1,3-dioxolan-2-yl)-2-(methoxymethoxy)benzoylamino]pyridine-2-carboxamide (3.10 g) is treated with a solution of TFA (20 mL) and water (20 mL) for 2 h before the solution is evaporated. The residue is slurried with ethyl acetate to provide a solid which is collected and washed. The solid is dispersed in ethyl acetate and extracted with a mixture of aqueous potassium carbonate and 1 N NaOH. The resulting organic phase is washed with very dilute HCl, dried and evaporated to afford the product as a solid (0.476 g), which is used directly without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH:51][C:12]([C@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)O)C(C)C
Reactant: C[C@H](N)c1nc2ccc(F)cc2s1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CC(C)OC(=O)N[C@@H](C(=O)N[C@@H](C)c1nc2ccc(F)cc2s1)C(C)C
Yield: 69 %

Procedure:
In 250 ml of toluene, 13.4 g (0.066 mol) of N-isopropoxycarbonyl-D-valine was dissolved. Thereto was added 14.3 g (0.144 mol) of N-methylmorpholine. Then was dropwise added at −10° C., 8.6 g (0.063 mol) of isobutyl chlorocarbonate. Thereto was added 22 g (0.06 mol) of (S)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate. A reaction and a post-treatment were conducted in the same manner as in Reference Example 1, and the hot toluene solution was filtered in a hot state to remove the insoluble matter. The filtrate was cooled, whereby crystals were precipitated. The crystals were collected by filtration and dried to obtain 15.8 g (yield: 69.3%) of isopropyl {(R)-1-[(S)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1ccccc1F
Product: COc1ccc2c(-c3ccccc3F)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][C:3]=1[CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16].CO[CH:23](OC)[CH2:24][CH:25](OC)OC>CCO>[F:19][C:14]([F:20])([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:12][C:3]1[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]2[CH:25]=[CH:24][CH:23]=[N:1][C:2]=12
Reactant: CCOC(=O)c1nc(CCC(F)(F)C(F)(F)F)c(N)[nH]1
Reactant: COC(CC(OC)OC)OC
Solvent: CCO
Product: CCOC(=O)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12

Procedure:
A solution of the intermediate from Step C (0.4356 g, 1.446 mmol) and 1,1,3,3-tetramethoxypropane (1.572 mL, 9.54 mmol) in dry EtOH (11.39 mL) was heated by microwave irradiation at 160° C. for 6 h. Another 3.3 eq. 1,1,3,3-tetramethoxypropane was added and the reaction was subjected to microwave irradiation at 160° C. for 6 h. Another 3.3 eq 1,1,3,3-tetramethoxypropane was added and the reaction was subjected to microwave irradiation at 160° C. for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude product was purified by silica gel chromatography using a hexanes/EtOAc gradient to afford the desired product, as a yellow solid. 1H NMR (500 MHz, CHCl3-d) δ 9.48 (dd, J=1.77, 0.4 Hz, 1H); 8.38 (dd, J=3.8, 1.8 Hz, 1H); 6.91 (dd, J=7.3, 3.8 Hz, 1H); 4.53 (q, J=7.1 Hz, 2H); 3.41-3.35 (m, 2H); 2.70-2.56 (m, 2H); 1.48 (t, J=7.1 Hz, 3H). m/z=337.9 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[CH3:24][S:25]([N:28]1[CH2:29][CH2:30][CH:31]([NH:34][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:32][CH2:33]1)(=[O:27])=[O:26]
Reactant: Clc1ncc2c(-c3ccccc3)n[nH]c2n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc3c(-c4ccccc4)n[nH]c3n2)CC1
Yield: 21 %

Procedure:
The compound was prepared from 6-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (Example 14) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid in an analogous manner as described in Example 4 and was purified by HPLC (Gilson) to give a free base (21% yield). MS (M+H)+, 373.24.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C(NC(C)C)(C)C.[Li].[C:14]1([Bi:20](Br)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH3:3][C:2]([Bi:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])[C:1]#[N:5]
Reactant: Br[Bi](c1ccccc1)c1ccccc1
Reactant: CC(C)C#N
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C#N)[Bi](c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 0.45 ml (5 mmole) of isobutyronitrile (Tokyo Kasei Co., Ltd.) was dissolved in 5 ml of THF, and the mixture was chilled to −78° C. under nitrogen atmosphere. Thereto was slowly added dropwise lithium diisopropylamine obtained above. The reaction mixture was stirred at −78° C. for 10 minutes and then heated to 0° C. Thereto was added dropwise a solution of 2.223 g (5 mmole) of diphenylbismuthanyl bromide prepared in Preparation Example 3 in 5 ml of THF.