Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[CH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)#N.[CH2:17]([OH:19])[CH3:18].[OH:20]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O>[CH2:17]([O:19][C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[CH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)=[O:20])[CH3:18]
Reactant: N#Cc1ccc(C=Cc2cccnc2)cc1
Reactant: CCO
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(C=Cc2cccnc2)cc1
Temperature: 120 °C

Procedure:
To 3(4-cyanostyryl) pyridine (0.5 g) was added 95% ethanol (20ml) and conc. H2SO4 (1 ml). The reaction was then heated at 120°C for 22 hrs. The reaction mixture was cooled, diluted with water and basified using sodium bicarbonate. The product was extracted with ether. Mpt 98°C.
Reaction SMILES: [Cl:1]CCl.P(Cl)(Cl)([Cl:6])=O.C([O:13][C:14]([C:16]([O:19]/[N:20]=[C:21](/[C:25]1[N:26]=[C:27]([NH2:30])[S:28][CH:29]=1)\[C:22](O)=[O:23])([CH3:18])[CH3:17])=[O:15])(C)(C)C.Cl>CN(C)C=O.C(OCC)C>[ClH:1].[C:14]([C:16]([O:19]/[N:20]=[C:21](/[C:25]1[N:26]=[C:27]([NH2:30])[S:28][CH:29]=1)\[C:22]([Cl:6])=[O:23])([CH3:18])[CH3:17])([OH:13])=[O:15]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(N)n1
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)Cl)c1csc(N)n1)C(=O)O
Reaction time: 0.5 h
Yield: 86 %

Procedure:
After cooling down a mixture of 2,000 ml of dichloromethane and 2,000 ml of diethyl ether to a temperature of 0° C. to 5° C., 55 ml of phosphorus oxychloride and 38 ml of N,N-dimethylformamide were sequentially added dropwise thereto. At the same temperature, the solution was stirred for 30 minutes, and 100 g of (Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-aminothiazol-4-yl)acetic acid was then added thereto, followed by further stirring the resulting solution for one hour. After cooling down the stirred solution to a temperature of −15° C. to −20° C., anhydrous hydrochloric acid was introduced at a rate of 500 ml/min. to 1,000 ml/min over one hour, followed by stirring the solution. Upon this stirring, the deprotection on the carboxy group was proceeded while beginning to deposit a solid material. The solid material was filtered, washed with 100 ml of dicholoromethane, and 100 ml of diethyl ether, in sequence, and then dried in vacuo, thereby yielding 85 g (86% yield) of the title compound as a white solid. Melting point (° C.): 153-158 (decomposition); 1NMR: (δ, DMSO-d6); 1.51(s, 6H), 7.19(s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][P:29](=[O:34])([OH:33])[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH2:39]([Sn:43]([CH2:57][CH2:58][CH2:59][CH3:60])([CH2:53][CH2:54][CH2:55][CH3:56])[C:44]1[N:45]=[N:46][N:47]([CH2:49][CH2:50][CH2:51]O)[CH:48]=1)[CH2:40][CH2:41][CH3:42].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl.C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][P:29](=[O:33])([O:34][CH2:51][CH2:50][CH2:49][N:47]4[CH:48]=[C:44]([Sn:43]([CH2:53][CH2:54][CH2:55][CH3:56])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:57][CH2:58][CH2:59][CH3:60])[N:45]=[N:46]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO)nn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCOP(=O)(Cc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccc(Br)nc4C(=O)NC)n3)c(OC)c2)OCC)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 205 mg, 0.331 mmol), 3-[4-(tributylstannanyl)-1H-1,2,3-triazol-1-yl]propan-1-ol (Compound 64B, 165 mg, 0.397 mmol) and DIPEA (0.17 mL, 0.993 mmol) in 1,2-dichloroethane (8 mL) was added (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (517 mg, 0.993 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with DCM (30 mL), washed with sat. aq. NaHCO3 (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ISCO system: MeOH/DCM=0-3%) to give the desired product, which was used in the following step. MS (ESI): m/z 1018.86 [M+H]+. UPLC: tR=1.22 min (UPLC-SQD: very non-polar—2 min).
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][OH:19])[CH3:16].C(O)(=O)C1C(=CC(=CC=1)C(O)=O)C(O)=O>C(CCCO)CCCCO.O[Ti]=O.O>[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][O:19][C:13](=[O:14])[C:3]1[C:4](=[CH:5][C:6](=[CH:1][CH:2]=1)[C:7]([OH:9])=[O:8])[C:10]([OH:12])=[O:11])[CH3:16]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCCC(CC)CO
Agent: O=[Ti]O
Agent: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Agent: OCCCCCCCCO
Solvent: O
Product: CCCCC(CC)COC(=O)c1ccc(C(=O)O)cc1C(=O)O
Temperature: 150 °C

Procedure:
193 g (1 mol) of trimellitic acid anhydride and 234 g (1.8 mol) of 2-ethylhexanol plus 0.2 g of octylene glycol titanate were placed in a one-liter round flask. The mixture was heated to 150° C. with stirring and the introduction of nitrogen gas, and the splitting off of water begins. Within 4 hours the temperature is raised to 220° C., the distillate is separated by means of a Vigreux column, the top temperature amounts to 100° to 105° C. The bath temperature is maintained until the top temperature falls below 80° C. The product has an acid number of 150±10 mg KOH/g. 1.7 mol of 2-ethylhexanol per mol of trimellitic acid is contained in the product.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH2:27].[C:33]([C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)#[N:34]>C(O)(=O)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH:27][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([C:33]#[N:34])=[CH:36][CH:37]=1
Reactant: Cc1n[nH]c(CN)c1Oc1cc(Cl)cc(Cl)c1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1n[nH]c(CNCc2ccc(C#N)cc2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 14 h
Yield: 3 %

Procedure:
Sodium triacetoxyborohydride (216 mg, 1.09 mmol) was added in one portion to a stirred solution of the pyrazole of Example 109 (300 mg, 0.850 mmol), 4-cyanobenzaldehyde (111 mg, 0.850 mmol) and acetic acid (3 drops) in dichloromethane (25 ml) at room temperature under nitrogen. The reaction was stirred for 14 hours and then washed with 1M aqueous sodium carbonate solution (2×10 ml) and brine (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (10 mg) as a colourless oil.
Reaction SMILES: C[C:2]1[C:3](Cl)=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[O:13]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:11][C:5]1[N:4]=[C:3]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)[CH:2]=[CH:10][C:6]=1[C:7]([NH:26][CH2:25][CH2:24][C:23]1[CH:22]=[CH:21][C:20]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:28][CH:27]=1)=[O:9]
Reactant: CN1CCNCC1
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Reactant: Cc1cc(C(=O)O)c(Cl)nc1Cl
Product: CN1CCN(c2ccc(C(=O)NCCc3ccc(Oc4ccccc4)cc3)c(Cl)n2)CC1

Procedure:
In analogy to example 21 methyl 2,6-dichloronicotinic acid was coupled with 4-phenoxyphenethylamine and then reacted with N-methylpiperazine. Yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(O)(=O)C>O>[C:10]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])(=[O:12])[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To 25 ml of 2,6-xylidine (0.20 mole) was added slowly a mixture of 25 ml of acetic anhydride (0.26 mole) and 25 ml of acetic acid (0.44 mole) under stirring at room temperature. The mixture was stirred for 30 minutes at room temperature and, then, diluted with water. The crystalline precipitate was collected by filtration to give 30.1 g (91%) of the title compound (m.p. 182°-184° C.; colorless needles).
Reaction SMILES: CNCCN(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].CC1[N:19]=[C:18]([CH:20]=[O:21])[CH:17]=[CH:16]C=1.C([N-]C(C)C)(C)C.[Li+].CI>C1COCC1.O>[CH2:11]([C:10]1[N:19]=[C:18]([CH:20]=[O:21])[CH:17]=[CH:16][CH:9]=1)[CH3:12]
Reactant: [Li]CCCC
Reactant: Cc1cccc(C=O)n1
Agent: CC(C)[N-]C(C)C
Agent: CNCCN(C)C
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc(C=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a solution of N,N,N-trimethylethylenediamine (4.29 mL, 33 mmol) in THF (20 mL) at -25° C. was added n-BuLi (13.2 mL, 2.5M in hexanes, 33 mmol). This solution was stirred 15 minutes, then transferred into a -78° C. solution of 6-methyl-2-pyridine-carboxaldehyde (3.63 g, 30 mmol) in THF (80 mL). After stirring 30 minutes at -78° C., a THF (50 mL) solution of lithium diisopropylamide (33 mmol) was added and the now dark red mixture was stirred 1 hour at -78° C. Methyl iodide (5.68 g, 40 mmol) in THF (10 mL) was added and reaction mixture was allowed to warm to r.t. for 4 hours. Water and 25% aq. NH4OAc were added, the crude product was extracted with EtOAc (2×) and solvents were evaporated. Purification by flash chromatography (from 5% to 10% EtOAc in hexanes) gave 660 mg of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:13]([NH:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Li+].[I-].N1C(C)=CC(C)=CC=1C>CCOCC>[CH3:18][C:15]1[N:14]=[C:13]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:12]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[CH:17][N:16]=1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOCC
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of [5-(4-methoxy-benzenesulfonyl)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethylphenyl)-amine (300 mg, 0.75 mmol), prepared as described in Example 1, LiI (2.0 g, 15 mmol) and 2,4,6-collidine (5 mL) was refluxed under N2 for 2 h and then cooled to room temperature. The reaction mixture was diluted with Et2O, and extracted (4×) with 2 N NaOH. The combined aqueous layers were washed with ether, neutralized with 3 N HCl to pH=7.0 and then were extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the desired product (271 mg, 93%) as a white solid: mp 246–248° C.; 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 8.30 (br s, 1H), 7.82 (d, J=8.7 Hz, 2H), 6.92 (s, 2H), 6.89 (d, J=8.7 Hz, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 2.03 (s, 6H); APCI MS m/z 384 [(M+H)+, calcd for C20H22N3O3S, 384.1].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4](Cl)[N:3]=1.[OH:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18].[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1>>[OH:30][B:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:29][C:2]3[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[N:3]=3)=[CH:28][C:23]=2[CH2:22][O:21]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(=O)CCCO
Reactant: N#Cc1cc(C#N)c(Cl)nc1Cl
Product: CC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(C#N)cc1C#N

Procedure:
This compound was prepared from 2,6-dichloropyridine-3,5-dicarbonitrile, 5-hydroxypentan-2-one, and benzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.7-1.73 (m, 2H), 2.04 (s, 3H), 2.35 (t, J=5.4 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 5.02 (s, 2H), 7.29 (dd, J=6.3, 1.5 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 7.81 (d, J=6.0 Hz, 1H), 8.94 (s, 1H), 9.3 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si](C)(C)C)=[C:11]([F:19])[C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25].[Br:26]Br.ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Br:26])=[C:11]([F:19])[C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2F)c(F)c(N)c1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2F)c(F)c(N)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
Methyl 4-amino-3-chloro-6-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-fluoropicolinate (2.5 g, 6.43 mmol) was dissolved in acetonitrile (32 mL) and bromine (3.31 mL, 64.3 mmol) was added. The reaction mixture was stirred at room temperature for 4 h at which time LCMS indicated the reaction was mostly complete. The reaction mixture was partitioned between dichloromethane and water and sodium thiosulfate (10.17 g, 64.3 mmol) was added. The aqueous phase was extracted with dichloromethane and the organic extracts were combined and concentrated under vacuum. The product was purified by flash chromatography (SiO2, eluting with 5-40% ethyl acetate in hexanes) to provide the title compound as a light yellow solid (1.62 g, 63.7%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.C(OC1C=CC=CC=1)CCCCCC.[CH2:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:22]([C:29]1[CH:30]=[CH:31][C:32]([C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:7])=[CH:33][CH:34]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCc1ccccc1
Agent: CCCCCCCOc1ccccc1
Product: CCCCCCCc1ccc(C(=O)CCC(=O)O)cc1
Yield: 70.2 %

Procedure:
The first step of Example 1 was repeated except that succinic anhydride (62.4 g) was replaced by 68.1 g thereof and heptyloxybenzene (100 g) was replaced by heptylbenzene (100 g), to obtain 3-(4-heptylbenzoyl)propionic acid (110 g). m.p.: 101.0°-103.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([CH2:19][NH2:20])[CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH2:19][CH:16]2[CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: NCC1CC1
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Yield: 90.6 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and cyclopropylmethylamine (0.34 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethyl)-benzenesulfonamide (0.50 g, 91%) was provided after purification. MS (ESI) m/z 358. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)cc2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)cc2)s1

Procedure:
Part A: Ethyl 5-(4-bromophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.80 gram, 3.94 mmol) is dissolved in methanol (20 mL) and a solution of KOH (0.65 gram (85%), 9.85 mmol) in water (20 mL) is added. The resulting mixture is heated at reflux temperature for 1 hour, poured into water and acidified with hydrochloric acid (1N solution). The formed precipitated material is collected by filtration and dried in vacuo at room temperature to give a quantitative yield of 5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-thiazole-2-carboxylic acid. Melting point: 94-95° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]([OH:30])(=[O:29])[CH2:25][CH2:26][C:27]#[CH:28]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:28]#[C:27][CH2:26][CH2:25][C:24]([OH:30])=[O:29])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: C#CCCC(=O)O
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#CCCC(=O)O)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-Chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 4-pentynoic acid according to the General Procedure A. tR=4.73 min. 1H NMR (DMSO-d) δ 12.2 (s, 1H), 8.15 (s, 1H), 7.28 (s, 1H), 6.80 (s, 2H), 5.33 (s, 2H), 3.73 (s, 3H), 3.31 (br. s, 2H), 2362 (br. t, 2H), 2.27 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH:6]1[N:7]([C:15](=[O:17])[CH3:16])[C:8]1[C:13]2=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].CN1CCOCC1.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>O1CCCC1>[C:1]([O:4][C:5]12[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH:6]1[N:7]([C:15](=[O:17])[CH3:16])[C:8]1[C:13]2=[CH:12][C:11]([O:14][C:32]([O:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:33])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC12CCN(C(C)=O)C1N(C(C)=O)c1ccc(O)cc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)OC12CCN(C(C)=O)C1N(C(C)=O)c1ccc(OC(=O)Oc3ccc([N+](=O)[O-])cc3)cc12
Reaction time: 72 h
Yield: 11.8 %

Procedure:
To the solution of 1,8-diacetyl-5-hydroxy-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl acetate (88 mg; 0.28 mmol) in N-methylmorpholine (62 μl, 0.56 mmol) and small amount of tetrahydrofuran, the 4-nitrophenyl chloroformate (112.9 mg; 0.56 mmol) dissolved in tetrahydrofuran was added. Reaction was carried out for 3 days under an argon atmosphere. The solvent was evaporated. The residue was purified by column chromatography (SiO2, cyclohexane/methylene chloride/methanol) to give 16 mg of title compound with 12% of yield.
Reaction SMILES: COC(C)(C)C.[C:7]([NH:26][C@H:27]([C@H:33]([OH:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:28](OCC)=[O:29])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[BH4-].[Na+]>O>[C:7]([NH:26][C@H:27]([C@H:33]([OH:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:28][OH:29])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C(=O)OCC)[C@H](O)CCCCCCCCCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)CCCCCCCCCCCCCCC
Temperature: 23 °C
Reaction time: 48 h
Yield: 95.3 %

Procedure:
A t-butyl methyl ether suspension (2 mL) containing ethyl (2R,3R)-2-octadecanoylamino-3-hydroxyoctadecanoate (100 mg. 0.16 mmol) synthesized in the same method as Example 17 and sodium borohydride (20.3 mg, 0.54 mmol) was stirred at 23° C. for 48 hours. After water (5 mL) was added thereto, the reaction mixture was separated at 40° C. to separate the organic layer. It was confirmed by comparative analysis of the obtained organic layer with sample product using HPLC that the organic layer contained 86.6 mg of the title compound (yield: 93%). HPLC analysis was carried out to find that anti-form:syn-form was 93:7 and the optical purity of the anti-form was 100% ee.
Reaction SMILES: [C:1]([C:3](=[N:7][O:8][CH3:9])[C:4](N)=[O:5])#[N:2].C(=O)(O)[O-:11].[Na+].Cl.[NH2:16][OH:17]>O>[C:4]([C:3](=[N:7][O:8][CH3:9])[C:1](=[N:16][OH:17])[NH2:2])([OH:11])=[O:5]
Reactant: CON=C(C#N)C(N)=O
Reactant: O=C([O-])O
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)O)C(N)=NO
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a suspension of 2-cyano-2-methoxyimino-acetamide (24.4 g, 0.19 mol) and sodium bicarbonate (32.2 g, 0.38 mol) in water, hydroxylamine hydrochloride (13.3 g, 0.19 mol) in water (18.4 g) was added dropwise at 80° to 85° C. The mixture was stirred at the same temperature for 3 hrs. Then, the reaction solution was concentrated followed by adjusting to pH 2.0 with concentrated hydrochloric acid and then cooling to separate crystals. The crystals were filtered off, washed with methanol (20 g) and dried to give 2-carboxy-2-methoxyimino-acetamidoxime (27.1 g). The crystal contained 14.8% of sodium chloride. Practical yield: 27.1×0.852=23.1 g. Yield: 74.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5].C(N(CC)CC)C.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:38])=[C:33]([CH:37]=1)[C:34](Cl)=[O:35]>ClCCl.O>[S:13]1[C:8]2[CH:9]=[CH:10][CH2:11][CH2:12][N:6]([C:4]([C:3]3[CH:16]=[CH:17][C:18]([NH:20][C:34](=[O:35])[C:33]4[CH:37]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=4[CH3:38])=[CH:19][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:15]=[CH:14]1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCC=Cc3sccc32)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCC=Cc3sccc32)c(Cl)c1
Reaction time: 48 h
Yield: 74.3 %

Procedure:
To a cooled solution of 0.20 g of 4-(2-chloro-4-aminobenzoyl)-5,6-dihydro-4H-thieno [3,2-b]azepine and 137 μl of triethylamine in 3 ml of dichloromethane is added a solution of 0.142 g of 5-fluoro-2-methylbenzoyl chloride in 1 ml of dichloromethane. The mixture is stirred under argon for 2 days and diluted with 30 ml of dichloromethane and 15 ml of H2O. The organic layer is separated and washed with 15 ml each of 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate, the filter pad washed with dichloromethane and the filtrate evaporated. The residue is crystallized from ethyl acetate to give 0.215 g of white crystals, m.p. 125°-132° C.