Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 197 °C
Yield: 85 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 10 parts of diphenyl phosphite are mixed and heated to 197° C. The elimination of water commences at this temperature and has ended when the internal temperature is 235° C. 31 parts of water are removed in the course of 8 hours. After distilling off excess α-naphthol and aniline, 372 parts of phenyl-α-naphthylamine are obtained at a boiling point of 202° - 204° C/5 mm Hg; the product has a melting point of 55° - 58° C and corresponds to a yield of 85% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])[CH3:2].CC[N:23](C(C)C)[CH:24]([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:20])[NH:23][CH:24]([CH3:26])[CH3:25])=[CH:16][CH:17]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnn(Cc2ccc(C(=O)O)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)N
Product: CCOC(=O)c1cnn(Cc2ccc(C(=O)NC(C)C)cc2)c1
Temperature: 23 °C

Procedure:
To a solution of 1-(4-carboxy-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester (50 mg, 0.153 mmol) in DCM (1 ml) were added DIPEA (40.1 μl, 0.230 mmol), HBTU (63.9 mg, 0.168 mmol) and isopropylamine (13 μl, 0.153 mmol). Reaction mixture was stirred over a weekend at 23° C. The solvent was evaporated, and the residual oil was dissolved in ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and brine. Organic layer was dried (sodium sulfate), filtered and evaporated to afford the title compound. HPLC (method G) Rt=1.761 min; UPLC (method F) Rt=0.79 min, MS [M+H]+316.3.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=O)[CH3:14]>C(O)C1C=CC=CC=1>[CH:5]1[CH:7]=[CH:9][C:13]([CH2:14][O:1][CH:2]2[O:10][CH:9]([CH2:11][OH:12])[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]2[OH:4])=[CH:2][CH:3]=1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(=O)Cl
Solvent: OCc1ccccc1
Product: OCC1OC(OCc2ccccc2)C(O)C(O)C1O
Temperature: 50 °C
Yield: 130 %

Procedure:
D-Mannose (30 g, 167 mmol) and acetyl chloride (13 mL, 167 mmol) was dissolved in benzyl alcohol (250 mL) and heated to 50° C. for 1 h. The resulting solution was concentrated by low pressure distillation. The resulting residue was purified by flash column chromatography (ethyl acetate/methanol, 9:1) and recrystallised from isopropanol/petrol to afford the title compound (29.34 g, 70%) as a white crystalline solid m.p. 126-127° C. [Lit 128-129° C.]; [α]D26+102.0 (c, 1.1 in MeOH); [Lit. [α]D18+73.1 (c, 1.4 in H2O)]; δH (400 MHz, CD3OD) 3.62 (1H, ddd, J4,5 9.5 Hz, J5,6 2.3 Hz, J5,6′ 5.5 Hz, H-5), 3.68 (1H, at, J9.3 Hz, H-4), 3.73-3.78 (2H, m, H-3, H-6), 3.85-3.88 (2H, m, H-2, H-6′), 4.75, 4.52 (2H, ABq, J11.6 Hz, CH2), 4.86 (1H, d, J1,2 1.8 Hz, H-1), 7.28-7.38 (5H, m, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)([O-])=O>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(N)c(N)c2)CC1

Procedure:
1-(3,4-dinitrobenzyl)-4-methylpiperazine (1 g) was dissolved in DMF:MeOH (1:1, 20 ml) and agitated with 10% Pd/C (50 mg) under an atmosphere of H, for 6 hours. The mixture was then filtered and evaporated to give a dark solid which was used immediately without any further purification.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 180 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
144 parts of α-naphthol, 150 parts of aniline and 5 parts of triphenylphosphite are mixed and first heated to 180° C. The reaction commences, with elimination of water. The water is removed by means of a water separator and the aniline evolved is returned. The temperature rises to 210° in the course of 4 hours. After a further 4 hours at 212° C, the elimination of water has ended (18 parts of H2O). The reaction mixture is cooled to 150° C and the excess aniline is distilled off under reduced pressure. Thereafter, 208 parts of phenyl-α-naphthylamine distil at 202° - 203° C/5 mm Hg; this product has a melting point of 55° - 58° C and corresponds to a yield of 95% of theory.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[CH2:5].[CH3:6][Si:7]([CH3:10])([CH3:9])Cl.C([Si](C)(C)C)CC=C.[BrH:19]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][Si:7]([CH3:10])([CH3:9])[CH3:6].[Br-:19]
Reactant: C=CCCBr
Reactant: Br
Reactant: C[Si](C)(C)Cl
Agent: C=CCC[Si](C)(C)C
Product: C[Si](C)(C)CCCCBr
Product: [Br-]
Yield: 90 %

Procedure:
4-Bromobutyltrimethylsilane was prepared by the procedure of Perklev, Chem. Abstr., 49, 1541 (1955), involving the preparation of the Grignard reagent from 4-bromo-1-butene, its reaction with trimethylchlorosilane to give 3-butenyltrimethylsilane, and free radical catalyzed HBr addition. The latter addition gave 90% primary bromide. Using inadequate initiator gave mainly secondary bromide.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21](F)=[CH:20][N:19]=[C:18]([NH:23]CCCC5CCNCC5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])CC1.[ClH:33].Cl.C1(NC(C2C3C=C(C4C(F)=CN=C(NC[CH2:59][CH2:60][CH:61]5[CH2:66][CH2:65][N:64]([CH3:67])[CH2:63][CH2:62]5)N=4)SC=3C=CC=2)=O)CC1.CNC(C1C2C=C(C3C([Cl:87])=CN=C(Cl)N=3)SC=2C=CC=1)=O>>[ClH:87].[ClH:33].[CH3:1][NH:4][C:5]([C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[C:21]([Cl:87])=[CH:20][N:19]=[C:18]([NH:23][CH2:59][CH2:60][CH:61]4[CH2:66][CH2:65][N:64]([CH3:67])[CH2:63][CH2:62]4)[N:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3F)cc12
Reactant: CN1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCN(C)CC4)ncc3Cl)cc12

Procedure:
Using the methods of 2-[5-fluoro-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 2-{5-fluoro-2-[3-(1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 444 (35Cl) and 446 (37Cl) [M(free base)+H].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=O)OC(C)(C)C.N1(OC2[N:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[N:40]=[CH:41][S:42][CH:43]=4)=[C:35]([F:44])[CH:34]=3)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:40]=[CH:41][S:42][CH:43]=3)=[C:35]([F:44])[CH:34]=2)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1Nc1ccc(-c2cscn2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.30 M in NMP, 1.00 mL, 0.300 mmol) in NMP (1 mL) was added to 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluoro-4-(thiazol-4-yl)phenylamino)pyrimidine-5-carboxamide (12 mg, 0.027 mmol). DIEA (0.050 mL, 0.29 mmol) was also added. The mixture was stirred at 90 C for 1 h. After being cooled to room temperature, TFA (1 mL) was added. The solution was stirred at room temperature for 60 min. The mixture was purified by HPLC to give the titled compound (5 mg). MS 428.4 (M+H). UV λ=229.8, 313.8 nm.
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[CH:5]([C:8]1[S:9][CH:10]=[C:11]([C:13]([N:15]2[CH2:20][C:19]3([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH:34]=O)[CH2:22][CH2:21]3)[O:18][CH2:17][CH2:16]2)=[O:14])[N:12]=1)([CH3:7])[CH3:6].C(O)(=O)C.[NH2:42][CH2:43][C@@H:44]([C:46]1[C:54]2[S:53][C:52](=[O:55])[NH:51][C:50]=2[C:49]([OH:56])=[CH:48][CH:47]=1)[OH:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:1]([OH:4])=[O:3].[OH:56][C:49]1[C:50]2[NH:51][C:52](=[O:55])[S:53][C:54]=2[C:46]([C@@H:44]([OH:45])[CH2:43][NH:42][CH2:37][C:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][C:19]3([O:18][CH2:17][CH2:16][N:15]([C:13]([C:11]4[N:12]=[C:8]([CH:5]([CH3:7])[CH3:6])[S:9][CH:10]=4)=[O:14])[CH2:20]3)[CH2:25][CH2:24]2)=[CH:47][CH:48]=1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: CC(=O)O
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCCC(C)(C)C=O)CC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCCC(C)(C)CNC[C@H](O)c4ccc(O)c5[nH]c(=O)sc45)CC3)C2)cs1
Product: O=CO
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Acetic acid (0.066 mL) was added to a mixture of 9-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2,2-dimethylnonanal (example 103, step d) (0.4 g) and (R)-7-(2-amino-1-hydroxyethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride (WO2007027134, example 1, step d) (0.3 g) with 3 Å molecular sieves in anhydrous methanol (10 mL). The mixture was stirred for 5 min then cooled to 0° C. Sodium triacetoxyborohydride (0.16 g) was added and the resulting mixture stirred at RT for 16.5 h. The solution was filtered then concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile and water and purified by preparative HPLC (Phenomenex Gemini®, Gradient: 10-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze-dried to give the titled compound as a white solid. Yield 0.10 g.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>O.CCO>[OH:14][NH:13][C:1]([C:3]1[C:4]2[CH:5]=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[NH:2]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cccc2[nH]ccc12
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
A mixture of 4-cyanoindole (0.64 g; 4.5 mmol), HCl×H2NOH (1.1 g; 15.8 mmol), and Na2CO3 (0.79 g; 7.43 mmol) in H2O (8 ml) and EtOH (2 ml) was gently stirred for 15 min, then refluxed for 6 h under N2. After cooling most of the EtOH was removed under reduced pressure and the product was extracted with EtOAc (3×10 ml). The organic phase was separated, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.74 g; 94%), as a creamy foam. 1H-NMR (DMSO-d6+CDCl3+CD3OD) 1.71 (broad s, H2O); 3.68 (HDO); 6.74 (d, 1H, J=3.1 Hz); 7.01 (tr, 1H, J=7.8 Hz); 7.12-7.2 (m, 2H); 7.3-7.4 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16]([OH:18])=O)[CH3:13].C(N(CC)CC)C.C(Cl)(Cl)[Cl:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:27])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:18])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: CCNCC(=O)O
Reactant: ClC(Cl)Cl
Reactant: S=C=Nc1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccc(Cl)cc2Cl)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 16 using 20.4 g of 2,3-dichlorophenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (20% ethyl acetate in hexane) The title compound (8.8 g) was obtained as a light peach solid, m.p. 144°-146° C. Anal. Calcd. for. C11H10Cl2N2O S: C, 45.69; H, 3.49; N, 9.69. Found: C, 45.81; H, 3.40; N, 9.58. Mass spectrum (CI, [M+H]+) m/z 289/29 1/293.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:18]3[C:19](O)=[N:20][CH:21]=[N:22][CH:23]=3)=[C:12]2[O:11][N:10]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:18]3[C:19]([Cl:27])=[N:20][CH:21]=[N:22][CH:23]=3)=[C:12]2[O:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3Cl)noc12
Product: Fc1ccc(-c2noc3c(-c4cncnc4Cl)ccnc23)c(Cl)c1
Temperature: 90 °C
Yield: 97.8 %

Procedure:
A suspension of 5-(3-(2-chloro-4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-ol (5.0 mg, 0.015 mmol) in phosphorus oxychloride (100 μl, 1.073 mmol) was heated at 90° C. for 1 h, then allowed to cool to room temperature. The solvent was evaporated to give the title compound (5.3 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccc(-n2ccnc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Yield: 87.3 %

Procedure:
150.7 g (0.560 mol) of 2,5-dichloro-4′-fluorobenzophenone, 114.4 g (1.68 mol) of imidazole, 100.6 g (0.728 mol) of potassium carbonate, and 840 mL of N,N-dimethyl acetamide were weighed in a 2 L three-necked flask equipped with a stirrer, thermometer, cooling pipe, and nitrogen inlet tube. The reaction solution was heated to 110° C. using an oil bath for 2 hours under a nitrogen atmosphere. After confirming the disappearance of raw materials by way of thin-layer chromatography, the reaction liquid was allowed to cool to room temperature. Thereafter, the reaction liquid was gradually added to 3 L of water, the product was solidified and filtered. The product obtained by filtering was dissolved in THF (1.2 L), toluene (4 L) was added, and the mixture was washed with a sodium chloride solution till the aqueous layer became neutral. The organic layer was dried using magnesium sulfate, and then the solvent was removed by an evaporator. The approximate yield amount was 180 g. The crude product was subjected to a recrystallization separating operation using a mixed solvent of 1 L toluene and 20 mL methanol heated at 80° C. to obtain 155 g of a white solid at a yield of 87%.
Reaction SMILES: [Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:20]=[C:21]=S.[Cl:23][C:24]1[C:25]([N:33]2[CH2:38][CH2:37][CH:36]([C:39]([F:42])([F:41])[F:40])[CH2:35][CH2:34]2)=[CH:26][C:27]([NH:31][CH3:32])=[C:28]([CH:30]=1)[NH2:29].CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:20][C:21]1[N:31]([CH3:32])[C:27]2[CH:26]=[C:25]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([F:41])([F:42])[F:40])[CH2:35][CH2:34]3)[C:24]([Cl:23])=[CH:30][C:28]=2[N:29]=1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Reactant: O=C(NCc1cc(F)c(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)cc(F)c2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to the procedure in Example 76 using N-(4-chloro-5-fluoro-3-isothiocyanatobenzyl)-1-trifluoromethyl-cyclopropane carboxamide (211 mg; 0.60 mmol), 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (184 mg; 0.60 mmol), DIC (78 mg; 0.60 mmol) and DMF (4 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:17][CH2:18][CH2:19][CH2:20][OH:21])(=[O:12])=[O:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:17][CH2:18][CH2:19][CH:20]=[O:21])(=[O:12])=[O:11]
Reactant: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a cooled (0° C.), stirred solution of 528 mg (1.44 mmol) of 3-[3-(2-methoxy-5-methylphenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 527 μL (3.02 mmol) of N,N-diisopropylethylamine and 307 μL (4.32 mmol) of anhydrous dimethyl sulfoxide in 6.0 mL of anhydrous dichloromethane was added 459 mg (2.88 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 16 h. The mixture was poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated. The resulting material was chromatographed on 35 g of silica gel with dichloromethane followed by 3% ethyl acetate-dichlorometharie to afford 320 mg (61%) of the title compound as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 9.83 (t, 1 H, J=1.4 Hz), 7.63 (d, 1 H, J=2.3 Hz), 7.40 (dd, 1 H, J=8.5, 2.3 Hz), 6.98 (d, 1 H, J=8.5 Hz), 6.59 (br s, 1 H), 6.55 (br s, 1 H), 6.46 (t, 1 H, J=2.1 Hz), 4.19 (t, 2 H, J=6.1 Hz), 3.98 (s, 3 H), 2.85 (td, 2 H, J=6.1, 1.4 Hz), 2.29 (s, 3 H) and 2.25 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([NH:11][CH2:12][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:5]([F:10])[C:6](=[N:8][NH2:9])[N:7]=1.[CH:18]1([CH2:23][C@H:24]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:25](O)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:25](=[O:26])[C@H:24]([CH2:23][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:28][N:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:37]=[O:38])[C:5]([F:10])=[C:4]([NH:11][CH2:12][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[N:3]=1
Reactant: NN=c1nc(Cl)[nH]c(NCc2cscn2)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2cscn2)c1F)OC1CCCCO1
Reaction time: 48 h

Procedure:
2-Chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone (0.105 g) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.182 g, 0.422 mmol) were dissolved in DMF (5 mL). NMM (0.21 mL, 1.91 mmol) was added, followed by HOAt (0.063 g, 0.463 mmol) and EDC (0.088 g, 0.459 mmol). After stirring for 2 days, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a maroon solid (0.1133 g). LCMS: (M+H)+=556.0.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCc1ccc(C(O)C(=O)c2ccccc2)cc1
Yield: 74 %

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and ethylbenzene (0.49 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 2 hours. The reaction mixture was extracted with ethylacetate, the extract was washed with saturated sodium hydrogen carbonate solution and brine, dried with sodium sulfate anhydrous, and then concentrated to obtain a yellow-colored oil. The oil was crystallized from a petroleum ether/diethylether to obtain 357.1 mg (74.0% yield) of 4'-ethylbenzoin.
Reaction SMILES: [C:1]([C:3]([C:18]1[S:22][C:21]([Br:23])=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[CH2:4][CH2:5][CH2:6]O[Si](C(C)(C)C)(C)C)#[N:2].C(C(C1SC(Br)=CC=1)(C(C)C)CCCO)#N.[C:40]([C:42]1[CH:43]=[C:44]([CH:54]=[CH:55][CH:56]=1)[O:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)#[N:41].C(C(C1C=CSC=1)(C(C)C)CCCN1CCN(CCOC2C=CC=C(F)C=2)CC1)#N>>[C:1]([C:3]([C:18]1[S:22][C:21]([Br:23])=[CH:20][CH:19]=1)([CH:15]([CH3:16])[CH3:17])[CH2:4][CH2:5][CH2:6][N:51]1[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][O:45][C:44]2[CH:54]=[CH:55][CH:56]=[C:42]([C:40]#[N:41])[CH:43]=2)[CH2:53][CH2:52]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCO[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Reactant: N#Cc1cccc(OCCN2CCNCC2)c1
Agent: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(F)c2)CC1)c1ccsc1
Agent: CC(C)C(C#N)(CCCO)c1ccc(Br)s1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1ccc(Br)s1

Procedure:
By using [4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-tert-butyldimethylsilane (700 mg) which was obtained in Example 114-5) described in JP-A 11-206862, 4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexanol (371 mg, 80%) was synthesized as a yellow oil in accordance with Example 114-8) described in JP-A 11-206862. From 105 mg of the resulting compound and 96 mg of 2-(3-cyanophenoxy)ethylpiperazine, the title compound was synthesized as a colorless oil in accordance with the production method described in Example 84 (138 mg, 62%).
Reaction SMILES: Br.Br[C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.[CH2:9]([O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:9]([O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:3]2[S:7][C:6]([NH2:8])=[N:5][CH:4]=2)=[C:15]([F:20])[CH:14]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(Oc2cnc(N)s2)c(F)c1
Temperature: 25 °C
Yield: 40.3 %

Procedure:
To a solution of 5-Bromothiazole-2-amine hydrobromide (1.55 g, 5.97 mmol) in acetone (100 mL) was added 3-fluoro-4-hydroxy benzoic acid ethyl ester (1.1 g, 5.97 mmol) and cesium carbonate (3.89 g, 11.94 mmol) under argon atmosphere and refluxed for 5 hrs. The reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated under reduced pressure. The residue was partitioned in between ethyl acetate and water. The layers were separated, the organic layer was washed with cold 2 N NaOH (10 mL), brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 4-(2-amino-thiazol-5-yloxy)-3-fluoro-benzoic acid ethyl ester (0.68 gm).