Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[CH:26]1([N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH:26]1([N:29]2[CH2:34][CH2:33][CH:32]([NH:21][C:17]3[C:18]([NH2:20])=[N:19][C:14]([C:7]4[C:8]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[N:5]([CH2:4][C:3]5[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=5[F:1])[N:6]=4)=[N:15][CH:16]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1
Reactant: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C1CCN(C2CC2)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1NC1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 182 mg (1.312 mmol) of 1-cyclopropyl-4-piperidinone were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-cyclopropyl-4-piperidinone, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added and the mixture was stirred vigorously for 10 min. Subsequently, the mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 165 mg of the title compound were obtained (60% of theory).
Reaction SMILES: C1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([F:22])=[CH:7][CH:6]=2)CC1.[CH2:23]([O:25][C:26](=[O:37])[C:27](=[CH:33]OCC)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24].[C:38]1([CH3:45])[C:39](C)=CC=CC=1>>[CH:45]1([C:33](=[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:37])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH:4][C:5]2[CH:6]=[CH:7][C:8]([F:22])=[C:9]([N:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]3)[N:10]=2)[CH2:38][CH2:39]1
Reactant: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2F)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccccc1C
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(N2CCN(C(=O)OCC)CC2)n1)C1CC1

Procedure:
A solution of 3.8 g (12.3 mmole) of 4-[6-(cyclo- propylamino)-3-fluoro-2-pyridinyl]-1-piperazine carboxylic acid, ethyl ester, 2.7 g (12.3 mmole) of diethyl(ethoxymethylene)malonate and 50 ml of xylene was refluxed for 24 hours. The solvent was removed in vacuo and the residue was chromatograhed over silica gel eluting with chloroform/ethyl acetate (80/20) to give 2.3 g of the title compound as a viscous oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](ON1C(=O)CCC1=O)([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29].C([O-])(O)=O.[Na+].Cl>O1CCOCC1.O>[C:28]([NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][C:12]1[CH:19]=[CH:20][C:9]([CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:10][CH:11]=1)([O:30][CH2:31][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:29]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C[C@H](N)C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine (818 mg, 2.16 mmol), Fmoc-OSu (727 mg, 2.16 mmol) and NaHCO3 (906 mg, 10.8 mmol, 5 equivalents) in 48 ml of dioxane-water (1:1) was stirred at room temperature overnight. The reaction mixture was then cooled to 0° C. and acidified with 180 ml of 0.2 M HCl. The reaction product was extracted with ethyl acetate (30 ml×3), and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (CDCl3-EtOAc-MeOH) to provide N-Fmoc-4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine as a white solid (650 mg, 50.7%). 1H NMR (DMSO) δ: 12.704 (1H, s, br), 7.786 (2H, d, J=7.32 Hz), 7.760 (1H, d, J=8.54 Hz), 7.658 (2H, t, J=7.81 Hz), 7.435˜7.200 (4H, m), 7.254 (4H, s), 4.586 (1H, s), 4.274˜4.081 (4H, m), 3.111˜3.040 (1H, dd, J=4.40, 13.67 Hz), 2.913˜2.815 (1H, dd, J=10.75, 13.92 Hz), 1.390 (1H, s), 1.380 (1H, s). FABMS (+Ve), m/z 602 [MH+], 546 [MH+−C4H8], 490 [MH+−2 C4H8]. Anal. calcd. for C20H29NO6: C, 66.90; H, 6.5; N, 2.3. Found: C, 69.40; H, 6.67; N, 2.24.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[CH3:36][NH:37][CH3:38]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:37]([CH3:38])[CH3:36])=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CNC
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid and dimethylamine hydrochloride. LCMS (M+H)+: m/z=487.3.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:11]([C:13]2[C:18]([CH:19]([CH3:21])[CH3:20])=[C:17]([O:22][CH3:23])[N:16]=[C:15]([O:24][CH3:25])[N:14]=2)=[O:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1.Cl>C(Cl)(Cl)Cl.CO>[CH:19]([C:18]1[C:13]([C:11]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([CH3:10])[CH:7]=2)[CH:3]=[O:2])=[O:12])=[N:14][C:15]([O:24][CH3:25])=[N:16][C:17]=1[O:22][CH3:23])([CH3:21])[CH3:20]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C(OC)OC)c2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=O)c2)n1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a stirred solution of (3-dimethoxymethyl-5-methyl-phenyl)-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-methanone (3.13 g, 8.36 mmol) in chloroform (30 ml) at room temperature, was added hydrogen chloride in methanol solution [prepared from methanol (30 ml) and acetyl chloride (4 ml)]. After stirring for 2 hr., the mixture was evaporated in vacuo. The residue was dissolved in ether, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, i) MC, ii) MC:EA (9:1)) to afford 2.3 g (84%) of a white solid. m.p. 111-113° C.; 1H NMR (300 MHz, CDCl3) δ 1.20 (6H, d, J=7.2 Hz), 2.50 (3H, s), 2.85 (1H, m), 3.93 (3H, s), 4.08 (3H, s), 7.94 (1H, s), 7.99 (1H, s), 8.08 (1H, s), 10.02 (1H, s).
Reaction SMILES: C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@@]2(O)O[C@H]([C@H](C(O)=O)[C@@H](O)C2)C[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H:58]([NH2:64])[C@H]2O)C=CC=CC=CC=CCCC=CC=C1.[CH2:66](O)[C@H:67]1[O:72][C@H:71]([O:73][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:70]([OH:85])[C@@H:69]([OH:86])[C@@H:68]1[OH:87]>CN(C)C=O>[CH3:58][NH:64][CH2:66][C@@H:67]([C@H:68]([C@@H:69]([C@@H:70]([CH2:71][OH:73])[OH:85])[OH:86])[OH:87])[OH:72]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CCCC=CC=CC=CC=C[C@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](N)[C@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/CC/C=C/C=C/C=C/C=C/[C@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](N)[C@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Solvent: CN(C)C=O
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 427 %

Procedure:
5 g of nystatin and 3.0 g of maltose were suspended in 50 ml of dimethyl formamide and next the procedure was carried out as in Example IV. 4.5 g of N-methylglucamine salt of N-glycosyl nystatin of E1 cm1% =580 at 304 nm and IC50 =0.45 mcg/ml were obtained. Original antibiotic exhibited: E1 cm1% =790 at 304 nm and IC50 =0.18 mcg/ml.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C([O-])(O)=O.[Na+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[C:32](Cl)=[O:33]>CC(C)=O>[CH3:41][O:40][C:36]1[CH:35]=[C:31]([CH:30]=[C:29]([O:28][CH3:27])[C:37]=1[O:38][CH3:39])[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])=[O:33]
Reactant: Nc1cc(C(=O)c2ccccc2)ccc1N1CCOCC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)Nc2cc(C(=O)c3ccccc3)ccc2N2CCOCC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28 g. of 3-amino-4-morpholino-benzophenone are dissolved in 560 ml. of acetone, and 17 g. of solid sodium hydrocarbonate are added. A solution of 25.4 g. of 3,4,5-trimethoxybenzoyl chloride in 260 ml. of acetone are added dropwise to the solution at room temperature, under vigorous stirring. The temperature of the reaction mixture rises with about 6° to 10° C. After the addition the mixture is stirred for additional 30 minutes at room temperature, then poured into ice water. The separated product is filtered off, washed with water, dried, and crystallized from a mixture of acetone and ether. 37.5 g. of 3-(3,4,5-trimethoxybenzoylamino)-4-morpholino-benzophenone are obtained; m.p.: 171°-172° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:23][CH:24]([F:26])[F:25])=[C:15]2[O:19][C:18]([CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]=12)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:25][CH:24]([F:26])[O:23][C:14]1[C:15]2[O:19][C:18]([CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]=2[C:11]([C:9]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)=[CH:12][CH:13]=1
Reactant: CC(C)c1cc2c(C(=O)Nc3ccncc3N)ccc(OC(F)F)c2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc2c(-c3nc4cnccc4[nH]3)ccc(OC(F)F)c2o1

Procedure:
1.8 g of N-(3-aminopyrid-4-yl)-7-difluoromethoxy-2-(1-methylethyl)benzofuran-4carboxamide are boiled with 4.0 g of p-toluenesulfonic acid in 50 ml of toluene for 3 h in a water separator. The cooled solution is extracted by shaking with 50 ml of 2 N sodium hydroxide solution, the separated aqueous phase is extracted a further two times with 50 ml of ethyl acetate each time, and the organic phases are combined, dried over ignited potassium carbonate and concentrated in vacuo. The residue is crystallized from ethanol/water. 1.7 g (100% of theory) of the title compound of m.p. 201° C. are obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>CN(C)P(N(C)C)(N(C)C)=O>[C:9]1([O:8][CH2:7][CH2:6][NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCOc1cccc2ccccc12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2cccc3ccccc23)cc1

Procedure:
A solution of 29.1 g of 2-(1-naphthyloxy)ethanol O-methanesulfonate and 33 g of ethyl p-aminobenzoate in 100 ml of hexamethylphosphoramide is heated at 100° C. for 16 hours. The solution is worked up as described in Example 3 to give the product. Recrystallization gives crystals, mp 124°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-].COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1ccccc1F
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2ccccc2F)n1

Procedure:
Following the general method described in example 2b, 2-[2-(2-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallisation the title compound was obtained as a brown crystalline material. MS: m/e=224 (M+).
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:38])[CH2:25][C@@H:26]([NH:34][C:35](=[O:37])[CH3:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([N:8]([C@H:16]([C@@H:24]([OH:38])[CH2:25][C@@H:26]([NH:34][C:35](=[O:37])[CH3:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N[C@H](CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
(2S,5S)-2-(N,N-Dibenzylamino)-5-acetylamino-1,6-diphenyl-3-hexanone (3.0 g, 5.944 mmol) was dissolved in methanol (15 ml). Sodium borohydride (1.80 g, 23.78 mmol) was slowly added to the resultant solution while chilling with ice water so as not to raise the temperature above 10° C., thereby conducting reaction. The reaction mixture was stirred at room temperature for 5 hours. To the reaction mixture, was added a 10% hydrochloric acid (10 ml) while chilling with ice water. After bubbling ceased, the mixture was extracted with ethyl acetate (50 ml). The extract was washed with an aqueous sodium chloride and dried over sodium sulfate. The solvent was distilled off, and the resulting crude product was recrystallized from a mixed solvent of ethyl acetate (1.5 ml) and n-hexane (6 ml), thereby obtaining the title compound (2.70 g, 86.1%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClC=C(Cl)Cl>[CH3:11][N:12]([CH3:16])[C:13]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:14]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1nc2ccccc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=C(Cl)Cl
Product: CN(C)C(=O)Nc1nc2ccccc2s1
Reaction time: 40 h
Yield: 97.7 %

Procedure:
Using 2-aminobenzothiazole (1.50 g), N,N-dimethylcarbamoyl chloride (1.29 g), aluminum chloride (1.60 g), and trichloroethylene (40 ml), the reaction is effected as in Example 1, except that the reflux is carried out for 40 hours. Thus, 1,1-dimethyl-3-(2-benzothiazolyl)urea (2.16 g) is obtained. Yield is 97.7%. Melting point is higher than 300° C. (after recrystallization from ethanol).
Reaction SMILES: C1(C)C=CC(S(OC[CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:27][CH2:26][CH:25]4[CH:20]([CH2:21][CH2:22][CH:23]([CH2:28][CH2:29][CH3:30])[CH2:24]4)[CH2:19]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[C:37]([F:42])[C:36]=1[F:43])[CH3:33].[C:44](=[O:47])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([O:47][CH2:44][CH:12]2[CH2:13][CH2:14][CH:15]([CH:18]3[CH2:27][CH2:26][CH:25]4[CH:20]([CH2:21][CH2:22][CH:23]([CH2:28][CH2:29][CH3:30])[CH2:24]4)[CH2:19]3)[CH2:16][CH2:17]2)=[C:37]([F:42])[C:36]=1[F:43])[CH3:33]
Reactant: CCCC1CCC2CC(C3CCC(COS(=O)(=O)c4ccc(C)cc4)CC3)CCC2C1
Reactant: CCOc1ccc(O)c(F)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1CCC2CC(C3CCC(COc4ccc(OCC)c(F)c4F)CC3)CCC2C1
Temperature: 70 °C
Reaction time: 5 h
Yield: 59.7 %

Procedure:
(4-(6-Propyldecahydronaphthalene-2-yl)cyclohexyl)methyl p-toluenesulfonate (3.5 g) prepared in the tenth step was dissolved in DMF (50 ml). 4-Ethoxy-2,3-difluorophenol (1.6 g) and potassium carbonate (2.2 g) were added, and the mixture was stirred at 70° C. for 5 hours. The reaction mixture was washed with water, and dried over anhydrous magnesium sulfate. The DMF was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-heptane=1/20 by volume) and then by recrystallization (solvent: Solmix/n-heptane=1/4 by volume) to give 2-(4-((4-ethoxy-2,3-difluorophenoxy)methyl)cyclohexyl)-6-propyldecahydronaphthalene (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].IC.[Cl-].[NH4+].[C:14](OCC)(=O)C>C1COCC1>[CH3:14][NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1c(Cl)cccc1Cl
Temperature: -40 °C
Yield: 96 %

Procedure:
2,6-Dichloroaniline (1.62 g, 10 mmol) in THF (5 mL) was cooled to −78° C. and treated with n-buthyllithium (8 mL of a 1.6 M solution in hexanes). After brief warming to −40° C. the solution was cooled again before addition of iodomethane (0.9 mL, ˜15 mmol). The mixture was allowed to warm to room temperature before addition of saturated ammonium chloride solution, extraction with ethyl acetate, drying over anhydrous MgSO4 and solvent evaporation. The resulting residue was purified by column chromatography (dichloromethane) to yield N-methyl-2,6-dichloroaniline (1.70 g, 96%). N-Methyl-2,6-dichloroaniline (0.86 g, 4.89 mmol) dissolved in ethyl acetate (10 mL) was added to an ice-cold solution of phosgene (5.0 mL of a 20% solution in toluene). Cooling was removed and the mixture stirred at room temperature for 10 min and then heated to reflux for 30 min. The solvent was removed and replaced by dichloromethane (20 mL) before drop-wise addition to a cooled (−40° C.) mixture of anhydrous hydrazine (0.64 g, 20 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours before addition of saturated sodium bicarbonate followed by phase separation and solvent removal to yield N-(2,6-dichlorophenyl)-N-methylhydrazinecarboxamide (1.06 g, 93%). The N-methylhydrazinecarboxamide product (500 mg, 2.14 mmol) was stirred with 4-chlorophenyl isocyanate (360 mg, 2.48 mmol) in dichloromethane (10 mL) at room temperature for 3 h. The resulting slurry was cooled (−10° C.), filtered, and washed with cold dichloromethane (10 mL) to give a white powder. A third of the product was treated with POCl3 (3 mL) and heated under reflux for 2½ hours, where after the yellow/brown solution was cooled and added to crushed ice (˜50 g) and neutralized by addition of ammonium hydroxide solution (25% m/V). Filtration and drying gave the crude product as an off-white powder (280 mg) which was purified by silica gel chromatography using 50%-75% EtOAc/hexanes to give 18 (122 mg, 48%).
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[N:21]=[C:22]=[S:23]>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[N:21]=[C:22]1[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][S:23]1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: ClCC[NH2+]Cc1ccccc1
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2Cc2ccccc2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[F:18][C:19]1[CH:20]=[C:21]([C@H:26]2[CH2:28]O2)[CH:22]=[CH:23][C:24]=1[F:25].O>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([C@@H:26]2[CH2:28][C@H:9]2[C:7]#[N:8])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Fc1ccc([C@H]2CO2)cc1F
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#C[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 75 °C

Procedure:
Potassium t-butoxide (21.5 g) and toluene (150 mL) were charged into a reaction vessel. Diethyl cyanomethylphosphonate (34.8 g) was added to the mixture with stirring and mixture was heated to 70-80° C. Then a mixture of (2S)-2-(3,4-difluorophenyl) oxirane (29 g) in toluene (150 mL) was slowly added to above reaction mass at 75-80° C. over a period of 30 minutes and the mixture was maintained for 11-12 hours for completion of reaction as monitored by TLC. After completion of reaction, mixture was cooled to 25-30° C. and water (300 mL) was added, the layers were separated. The aqueous layer was back extracted with toluene (150 mL). The organic layers were combined and washed with water (300 mL). The combined organic layer was subjected to complete distillation under vacuum at below 55-60° C. to afford the compound which was purified by column chromatography to afford the title compound of about 97% HPLC purity.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([O:9][C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOCC>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:21](=[O:23])[CH:1]=[CH2:2])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Product: C=CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
Vinylmagnesium bromide (1M in tetrahydrofuran) was cooled under N2 atmosphere to -10° C. and treated in portions with 10 g (37.7 mmol) of N-(t-butyloxycarbonyl)-L-phenylalanine. The resulting solution was stirred at -10° C. for 5 h, and poured into a rapidly stirring mixture of ice, 10% aqueous citric acid and ether. The mixture was separated, and the organic phase was washed sequentially with water, two portions of aqueous NaHCO3, and saturated brine; dried over MgSO4 ; and concentrated in vacuo. Silica gel chromatography of the residue using 4:1 hexane:ethyl acetate provided 3.63 g (35%) of the desired compound (Rf 0.33, 3:1 hexane:ethyl acetate). 1H NMR (CDCl3) δ 1.41 (s, 9 H), 2.98 (dd, J=14, 6 Hz, 1 H), 3.15 (dd, J=14, 6 Hz, 1 H), 4.86 (q, J=8 Hz, 1 H), 5.23 (br d, 1 H), 5.85 (dd, J=9, 2 Hz, 1 H), 6.35 (dd, J=18, 2 Hz, 1 H), 6.45 (dd, J=18, 9 Hz, 1 H), 7.10 (br d, 2 H), 7.25 (m, 3 H). Mass spectrum: (M+H)+ =276.