Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:34]([C:36]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[NH2:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:35][NH:34][C:36]2[N:41]=[N:40][C:39]([C:42]3[CH:43]=[CH:44][C:45]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:46][CH:47]=3)=[CH:38][CH:37]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc(NN)nn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(-c2ccc(NNC(=O)Cc3ccc(Cl)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of 2-(4-chlorophenyl)acetic acid (1.07 mmole), HOBT (1.07 mmole), and EDCI hydrochloride (1.61 mmole) in DMF (7 mL) were added N-(4-(6-hydrazinylpyridazin-3-yl)phenyl)methanesulfonamide (1.07 mmole) in 10 mL of DMF followed by diisopropylethylamine (3.77 mmole). The resulting mixture was stirred at room temperature for 22 hours and evaporated in vacuo. The desired product N-(4-(6-(2-(2-(4-chlorophenyl)acetyl)hydrazinyl)pyridazin-3-yl)phenyl)methanesulfonamide was precipitated out from water.
Reaction SMILES: FC(F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:16][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[CH:3][N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)ccc1F
Yield: 64.9 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (277 mg, 1.45 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 416 mg, 1.32 mmol), DIPEA (226 mg, 1.58 mol), HOBT (216 mg, 1.98 mol) and HATU (753 mg, 1.98 mol) in DMF (6 mL), using a procedure analogous to that described in Example 1 Step C, except for the purification method. The compound was purified by preparative TLC (silica gel, 20% hexane in ethyl acetate, then 10% methanol in dichloromethane) to give 360 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 2.62 (m, 2H), 2.88 (m, 2H) 3.88-4.16 (m, 5H), 4.73 (s, 1H), 4.85 (m, 1H) 5.26-5.39 (m, 1H) 6.90 (bs, 1H), 7.06(m, 2H), 7.24(m, 1H). ESI-MS 489 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[C:63]=3[Cl:69])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])[C@@H:41]([O:52][C:53]2[N:58]=[CH:57][N:56]=[C:55]3[N:59]([C:62]4[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[C:63]=4[Cl:69])[N:60]=[CH:61][C:54]=23)[CH2:40][O:39][CH2:38][CH2:37][OH:36])=[N:46][CH:47]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)[C@H](COCCO)Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (0.661 mL, 0.66 mmol) was added dropwise to a stirred solution of (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (420 mg, 0.55 mmol) in THF (15 mL) over a period of 1 minute. The resulting solution was stirred at ambient temperature for 3 hours. Saturated ammonium chloride (20 mL) was added to the reaction mixture which was then diluted with EtOAc (25 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were concentrated to remove most of the MeCN and then EtOAc was added. The organic phase was washed sequentially with saturated NaHCO3 and water the organic layer was evaporated to dryness to afford the product (120 mg, 41.6%). 1H NMR (400 MHz, CDCl3) δ 3.75 (4H, m), 4.16 (1H, dd), 4.22 (1H, dd), 6.06 (1H, t), 7.42 (2H, m), 7.66 (2H, m), 8.20 (2H, m), 8.43 (1H, d), 8.58 (1H, s), 9.17 (1H, s); m/z (ES+) (M+H)+=525; HPLC tR=2.32 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH3:13])[C:9](O)([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:21])CC>ClCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH3:13])[C:9]([F:21])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(C)(C)O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(C)(C)F
Temperature: -76 °C
Reaction time: 1.5 h
Yield: 110.2 %

Procedure:
In a dry round-bottomed flask, ((R)-2-hydroxy-1,2-dimethyl-propyl)-carbamic acid tert-butyl ester (534 mg, 2.36 mmol) was dissolved in dichloromethane (22 ml). The solution was cooled to −76° C. and DAST (0.34 ml, 2.57 mmol) was added dropwise. The reaction mixture was stirred at −76° C. for 1.5 h then quenched with saturated aqueous NaHCO3 (5 mL), warmed to room temperature and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 534 mg of ((R)-2-fluoro-1,2-dimethyl-propyl)-carbamic acid tert-butyl ester as a yellow oil which was used without further purification.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][CH:25]([NH2:34])[CH:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:34][C@H:25]([CH3:24])[C@@H:26]([OH:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:18])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(N)C(O)c1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1ccccc1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with (1S,2R)-(+)-norephedrine as in EXAMPLE 1, Part C. HPLC: RT=10.13 min. MS (ESI−): mass calcd. for C22H19ClN4O4S2, 502.05; m/z found, 501 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.69 (s, 1H), 8.37 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.73 (d, J=2.0, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.41-7.29 (m, 5H), 7.24 (d, J=8.4, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.28 (br d, J=8.3, 1H), 4.98 (d, J=3.0, 1H), 4.45 (ddq, J=8.3, 6.9, 3.0, 1H), 2.60 (br s, 1H), 1.05 (d, J=6.9, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=[C:15]1C(OCC)=O>>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: COC(=O)c1ccc2ccn(C)c2c1
Yield: 95 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting methyl indole-6-carboxylate for the ethyl indole-2-carboxylate, the title compound (2.5 g, 95%) was obtained as white solid: MS (ES) m/e 190.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:4]=[N:3]1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: Cn1cc(-c2nc(C(=O)O)cs2)cn1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cnn(C)c2)n1
Yield: 76 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (0.254 g, 1.215 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.457 mmol). The product was triturated using diethyl ether. Yield 76%. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (d, 3H), 3.90 (s, 3H), 4.35 (dd, 1H), 4.42 (dd, 1H), 4.50 (m, 1H), 6.96 (d, 1H), 7.85 (d, 1H), 7.86 (d, 1H), 7.93 (d, 1H), 7.93 (dd, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.34 (d, 1H), 8.34 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH:27]O.[OH-].[Na+]>CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH2:26])=[O:27])=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C#N)nc2)c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(N)=O)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of with 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carbonitrile (50.0 mg, 0.141 mmol) in DMSO (281 μL) was slowly added to a solution of hydrogen peroxide (10.0 μL, 0.326 mmol) and sodium hydroxide (5 M, 56.3 μL, 0.281 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was filtered, diluted with DMF, and directly purified by reverse phase HPLC (5-95% acetonitrile in water+0.5% TFA) to yield 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxamide. MS APCI calc'd for C18H15F3N5O [M+H]+ 374. found 374. 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 8.65 (d, J=5.6 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H), 8.09 (d, J=8.5, 1H), 7.98 (s, 1H), 7.39 (s, 1H), 7.19 (s, 1H), 7.09 (d, J=5.5 Hz, 1H), 2.47 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:42]1[N:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:29])([F:31])[F:30])[CH:22]=4)=[O:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:6][C:5]([C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2)OC1(C)C
Reactant: Clc1ncccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ncc(-c2ncccn2)cc1-c1cc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Temperature: 25 °C
Yield: 18.5 %

Procedure:
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-[4-chloro-3-(trifluoromethyl)phenyl]urea (194 mg, 0.33 mmoles) and 2-chloropyrimidine (38 mg, 0.3 mmoles) was added to a mixture of 6 ml of dioxane and 2 ml of 2M aqueous Sodium Carbonate. Next, Palladium(II) Acetate (10 mol %, 7 mg) and Triphenylphosphene (20 mol %, 16 mg) was added, followed by 2 ml of dioxane. Dry nitrogen was bubbled through the resulting solution for 15 minutes. Following this, the reaction mixture was set up with a reflux condenser, under nitrogen atmosphere, and heated at 95 C overnight. The reaction was then cooled to room temperature and 40 ml of ethyl acetate was added. The mixture was transferred to a separatory funnel and extracted with saturated Sodium Bicarbonate (3×40 ml) followed by saturated NaCl (3×40 ml). The organic layer was dried with anhydrous Sodium Sulfate, loaded onto silica and columned using ethyl acetate/hexanes, to give 30 mg of the product. 1H NMR (<dmso>) δ: 9.19 (s, 1H), 9.02 (d, J=2.1 Hz, 1H), 8.99 (s, 1H), 8.83 (d, J=4.7 Hz, 2H), 8.47 (d, J=2.1 Hz, 1H), 8.14 (dd, J=13.8, 2.1 Hz, 2H), 7.90 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 7.58-7.66 (m, 2H), 7.41 (dd, J=8.8, 2.1 Hz, 1H), 7.35 (t, J=4.8 Hz, 1H), 6.71 (s, 2H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.CI>C1COCC1.CCCCCC>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH3:1])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (LDA) in THF (1 liter), which had been prepared from diisopropylamine (52 g) and a 1.6 M solution of n-butyl lithium in hexane (319 ml), was added dropwise a solution of ethyl 4-chlorophenylacetate (97.3 g) in THF (100 ml) at a temperature of -45° to -40° C. under an atmosphere of nitrogen gas. At the same temperature, the reaction mixture was stirred for 0.5 hours, and methyl iodide (73 g) was added dropwise thereto, followed by allowing the temperature to gradually increase to room temperature. The reaction mixture was poured into ice-water and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure to give ethyl 2-(4-chlorophenyl)propionate (yield, 89.4 g), b.p., 108°-114° C. at 1.0 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH3:15])[C:11](O)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:14][CH3:15])[CH2:11][OH:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 20.9 g of 2-(4-nitrophenyl)butyric acid in 500 ml of dry tetrahydrofuran was added, dropwise, 1.1 equivalents of 10 M borane-dimethylsulfide complex in 100 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 1.5 hours and then refluxed for 1.5 hours and finally cooled to room temperature. Methanol (10 ml) was added, the mixture was stirred for 30 minutes, and the solvent was then evaporated under reduced pressure. The residue was dissolved in 100 ml of methanol and the solvent was evaporated and this procedure was repeated three (3) times. The resulting oil was purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane to give 2-(4-nitrophenyl)butanol as a light-yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9](OC)=[O:10])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][CH2:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:5]=1
Reactant: COCc1nn(-c2cccc(OC)c2)cc1C(=O)OC
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCc1nn(-c2cccc(OC)c2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
A solution (5 mL) of methyl 3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxylate (1.1 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (10 mL) of lithium aluminum hydride (0.25 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (0.38 mL), 1N aqueous sodium hydroxide solution (1.9 mL) and water (0.38 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (0.68 g) of 3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (15 mL), manganese dioxide (1.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (0.30 g, 32%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15]I)=[O:9])=[CH:4][CH:3]=1.CO.[CH3:19][NH2:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][NH:20][CH3:19])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CI
Reactant: CN
Solvent: CO
Product: CNC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 44 h
Yield: 59 %

Procedure:
The title compound (80 mg, 0.20 mmol) produced in step (ix) of Reference Example 8 was dissolved in 1 ml of a 40% methylamine methanol solution, and the mixture was stirred at room temperature for 44 hr. The reaction solution was concentrated under the reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=5:1:0.1) to give 36 mg (yield 59%) of the title compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11].F[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:24]=2[N:25]=1>O>[F:8][C:9]([F:13])([F:12])[CH2:10][O:11][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:24]=2[N:25]=1
Reactant: OCC(F)(F)F
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A mixture of 0.06 g of 55% sodium hydride (in oil) and 2 ml of DMF was stirred at room temperature. To the mixture, a mixture solution of 0.13 g of 2,2,2-trifluoroethanol and 0.5 ml of DMF was added. The mixture solution was stirred at the same temperature for 15 minutes, and then 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole was stirred at room temperature for one hour. Water was added to the reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.27 g of 2-[3-(2,2,2-trifluoroethyl)oxypyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 39”).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.C([N-]C(C)C)(C)C.[Li+].[CH:28](=[O:30])[CH3:29].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH:28]([OH:30])[CH3:29])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC=O
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)C1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
In a round bottom flask, 2-chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (0.840 g, 3.0 mmol) was dissolved in dry tetrahydrofuran (12 mL), cooled to −78° C., then added 2.0 M lithium diisopropyl amide in tetrahydrofuran (6.0 mmol) drop wise. After 30 minutes, acetaldehyde (1.056 g, 24.0 mmol) in 6.0 mL tetrahydrofuran was added slowly drop wise to it, continued stirring for 60 minutes. After disappearing the starting material, cooled the reaction flask to −78° C., then quenched with sat. ammonium chloride solution (3 mL). At room temperature, the resultant reaction mixture was taken into ethyl acetate (50 mL), washed with 0.1 N HCl, ammonium chloride solution and finally with water, dried over sodium sulphate and evaporated. Purified the product using column chromatography with hexane:ethyl acetate mixtures to give the product (0.842 g, 86%). [M+H] calculated for C15H21ClN4O2, 325; found 325.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>C(O)C.O>[I:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccccc1I
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Oc1ccccc1I
Yield: 98 %

Procedure:
A solution of 1-(2-iodophenoxy)-2-nitrobenzene (9.60 g, 28.1 mmol) and SnCl.2H2O (13.0 g, 56.0 mmol) in ethanol (25 mL) and water (5 mL) was refluxed until no starting material remained (˜1 h). The ethanol was removed in vacuo and the aq layer was basified to pH>10 and extracted with CH2Cl2 (4×10 mL). The combined organic layers were dried over Na2SO4, and the solvent was removed to give a crude 2-(2-Iodophenoxy)benzenamine (8.57 g, 98%), which was used for the next step without purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=[O:3].[CH2:15]([OH:19])[CH2:16][CH2:17][OH:18]>>[CH3:14][O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:18][CH2:17][CH2:16][CH2:15][OH:19])=[O:3]
Reactant: COc1ccc(OC(=O)Cl)c(OC)c1
Reactant: OCCCO
Product: COc1ccc(OC(=O)OCCCO)c(OC)c1

Procedure:
The reaction of 2,4-dimethoxyphenyl chloroformate with 1,3-propanediol yields 1-(2,4-dimethoxyphenoxycarbonyloxy)-3-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][C:24]#[CH:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:29](=O)([O-])[O-].[K+].[K+].CI.ClCCl.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[N:21]([CH3:29])[C:20]3[C:19](=[O:22])[N:18]([CH2:23][C:24]#[CH:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCn1c(=O)c2[nH]c(C#Cc3ccc(OC)c(OC)c3)nc2n(CC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: C#CCn1c(=O)c2c(nc(C#Cc3ccc(OC)c(OC)c3)n2C)n(CC)c1=O

Procedure:
A mixture of 2.0 g (5.3 mmol) of 8-(3,4-dimethoxyphenylethynyl)-3-ethyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione, potassium carbonate (0.83 g, 6 mmol) and methyl iodide (0.6 ml, 10 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 0.5 h (TLC-control: dichloromethane/methanol, 9.5:0.5). The product was precipitated by addition of water (100 ml), filtered under reduced pressure, was washed with water and dried at 70° C. Further purification was achieved by column chromatography on silica gel (eluent: dichloromethane/methanol, 9.5:0.5) and subsequent crystallization from dichloromethane/petroleum ether. Yield: 1.76 g, 80% (crude product); m.p.: 221.5° C.