Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:36]>O1CCCC1.ClCCl>[ClH:36].[OH:1][C@@H:2]([CH2:3][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: C1CCNC1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H](O)CN2CCCC2)c1
Temperature: 45 °C
Yield: 87.3 %

Procedure:
To (R)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (250 mg, 0.61 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (969 mg, 9.11 mmol) followed by pyrrolidine (0.51 mL, 6.1 mmol). The reaction mixture was heated in a 45° C. oil bath for 3.75 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml) and washed with water (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (233 mg, 0.48 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.42 mL, 0.53 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (240 mg, 76%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.60 (br s, 1H), 8.20 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.80 (m, 5H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.5, 2.0 Hz, 1H), 4.57-4.53 (m, 1H), 4.49-4.46 (m, 1H), 4.27 (br s, 1H), 3.25-2.75 (br m, 6H), 1.85 (br s, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B)>99% (AUC), tR=15.1 min; [α]23D −11.3° (c 0.11, Methanol).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][C:4]=1[CH3:13])=[O:2].CC(CC)=C.[OH2:19].P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[ClH:30]>CC(O)(C)C.O>[Cl:30][C:5]1[C:4]([CH3:13])=[C:3]([C:1]([OH:19])=[O:2])[NH:7][C:6]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O
Reactant: CCOC(=O)c1cc(C)c(C=O)[nH]1
Reactant: Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: C=C(C)CC
Product: CCOC(=O)c1[nH]c(C(=O)O)c(C)c1Cl
Reaction time: 3 h

Procedure:
To a solution of ethyl 5-formyl-4-methyl-1H-pyrrole-2-carboxylate (0.40 g, 2.21 mmol) in t-BuOH (25 mL) was added 2-methylbutene as a 2M solution (38 mL, 76.0 mmol). In a separate flask sodium dihydrogen phosphate monohydrate (2.1 g, 15.2 mmol) and sodium chlorite (1.8 g, 19.9 mmol) were dissolved in water (25 mL). The aqueous solution was added to the alcoholic reaction mixture dropwise and stirred for 3 h. Additional sodium dihydrogen phosphate monohydrate (1.05 g, 7.73 mmol) and sodium chlorite (0.9 g, 9.95 mmol) dissolved in water (10 mL) were added and the reaction mixture stirred an additional 2 h. The solution was acidified with aqueous 5% HCl to a pH ˜4 and extracted with EtOAc (3×25 mL). The organic layers combined, dried over sodium sulfate, filtered and the solvent evaporated. Purification by column chromatography twice afforded 4-chloro-5-[(ethyloxy)carbonyl]-3-methyl-1H-pyrrole-2-carboxylic acid (0.10 g, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.32 (br. s., 1H) 4.24 (q, 2H) 2.19 (s, 3H) 1.28 (t, 3H). MS: m/z 232.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>C(OCC)(=O)C>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[N:3]=[CH:4][C:5]([C:6]([NH2:8])=[O:7])=[CH:9][CH:10]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc(C(N)=O)cn2)CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of 6-chloronicotinamide and 3 ml of 1-ethylpiperazine was stirred at 110° C. for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford 0.10 g of the title compound.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[CH:27]=[N:26][C:7]([CH2:8][C@H:9]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[NH2:10])=[CH:6]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([NH:10][C@@H:9]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH2:15][CH2:14]3)=[O:12])[CH2:8][C:7]3[N:26]=[CH:27][N:5]([CH3:4])[CH:6]=3)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)Cc3cn(C)cn3)CC2)CC1
Agent: Cl
Product: CN1CCC(C2CCN(C(=O)[C@@H](Cc3cn(C)cn3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-(1-methyl-D-histidinyl)-4-(1-methylpiperidin-4-yl)piperidine trihydrochloride and indole-6-carboxylic acid (23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12]O.N1C=CC=CC=1.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].C(Cl)[Cl:28]>>[Cl:28][CH2:12][CH:11]([O:14][S:23](=[O:25])(=[O:24])[NH:22][CH3:21])[CH2:10][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CNS(=O)(=O)Cl
Reactant: COc1ccccc1OCC(O)CO
Reactant: ClCCl
Solvent: c1ccncc1
Product: CNS(=O)(=O)OC(CCl)COc1ccccc1OC
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of 109.3 g (0.55 mole) of glyceryl guaiacolate in 177 ml (2.20 moles) of pyridine and 700 ml methylene chloride was added to a solution of 283 g (2.20 moles) of methylaminosulfonyl chloride in 700 ml of methylene chloride. The addition was made over one hour at 15°-22° C. The solution was stirred at 23° C. for two hours then washed with 3×500 ml water. The methylene chloride solution was dried over type 3A molecular sieves. The mixture was filtered and the filtrate diluted with 140 ml of ethyl acetate. The solution was chromatographed on 2 kg of silica gel using 10% ethyl acetate:methylene chloride solution as eluent. The first 3×750 ml fractions were combined and concentrated to 77.3 g of brown oil. The oil was redissolved in 400 ml of 10% ethyl acetate:methylene chloride solution and chromatographed on 1.5 kg of silica gel. A total of 9×250 ml fractions were collected that showed only one spot on TLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Br:12]Br>O1CCOCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][C:3]=1[OH:11]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: C1COCCO1
Product: Nc1c(O)cc(Br)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
As shown in step 6-iii of Scheme 6, to a solution of 2-amino-3-nitrophenol (5.00 g, 32.4 mmol) in dioxane (50 mL) was added bromine (6.22 g, 2.01 mL, 38.9 mmol). The mixture was stirred for 2 hours and a precipitate formed, which was collected and washed with dioxane and ether. The resulting yellow solid treated with a saturated NaHCO3 solution, which was extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 2-amino-5-bromo-3-nitrophenol (compound 1015) as a brown solid. This material was carried on as is in subsequent reactions without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH2:21])[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].C1OC1C.[Cl:27][CH:28]([Cl:42])[C:29]([O:31][NH:32][CH:33]([C:37]1[CH:41]=[CH:40][S:39][CH:38]=1)[C:34](Cl)=[O:35])=[O:30]>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:34](=[O:35])[C:33](=[N:32][O:31][C:29](=[O:30])[CH:28]([Cl:27])[Cl:42])[C:37]3[CH:41]=[CH:40][S:39][CH:38]=3)[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(ONC(C(=O)Cl)c1ccsc1)C(Cl)Cl
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC1CO1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3ccsc3)[C@H]2SC1
Temperature: 0 °C

Procedure:
To an ice cold solution of t-butyl 3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylate (1.59 g) and propylene oxide (3.5 mls) in ethyl acetate (15 mls) was added with stirring a 1-M solution of 2-dichloroacetoxyamino-2-(thien-3-yl) acetyl chloride (syn-isomer) (5.3 ml.) in ethyl acetate. After 11/2 hrs. at 20° C. the solution was washed with 2N-HCl, saturated sodium bicarbonate solution and brine. The organic layer was dried and evaporated to give t-butyl 3-acetoxymethyl-7β-[2-dichloroacetoxyimino-2-(thien-3-yl)acetamido]ceph-3-em-4-carboxylate (syn-isomer) as a white foam, (2.8 g, 100%), [α]D +47.0° (c 0.9, DMSO), λmax. (ethanol) 253 nm (ε 13,900), νmax. (CHBr3) 3580 (OH), 3410 (NH), 1790 (β-lactam), 1728 (OCOCH3), 1720 (COO But) and 1700 and 1520 cm.-1 (CONH); τ (CDCl3) values include 2.11 to 2.7 (m; thienyl protons), 7.92 (s; OCOCH3), 8.48 (s; But).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:20]1[CH2:24]C[CH2:22][CH2:21]1>CS(C)=O>[CH2:21]([O:20][CH2:24][N:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: C1CCOC1
Reactant: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC#Cc1cc(C)nc(N(COCC)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 2-anilino-4-methyl-6-(1-propynyl)-pyrimidine (2.5 g) in dimethyl sulfoxide (2.5 ml) were added to a suspension in 50 ml of tetrahydrofuran of 0.5 g of sodium hydride (60%) of which oily component was removed, and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, 1.5 g of chloromethyl ethyl ether was added thereto and the resulting mixture was stirred for 5 hours. The reaction mixture was poured into water and extracted with 150 ml of toluene. The toluene layer was washed wit water, dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The rsidue was purified by silica gel column chromatography to obtain 1.6 g (yield: 62%) of 2-(N-ethoxymethylanilino)-4-methyl-6-(1-propynyl) pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[N:2].Cl.CCOCC>CO.[Pd]>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][N:6]=1
Reactant: COc1cc(C#N)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cc(CN)ccn1
Reaction time: 8 h

Procedure:
4-Cyano-2-methoxypyridine (1.7 g) was dissolved in MeOH (50 ml) and conc. HCl (4.96 ml) was added. Pd/C (10%) was added and H2 was added and let stand overnight. The solids were filtered through Celite® and the cake was washed with MeOH (˜250 ml). Concentration in vacuo produced an oil which was dissolved in MeOH (˜20 ml). Et2O (200 ml) was added and stirred for 1 h. The resulting precipitate was filtered and washed with Et2O to afford (2-methoxypyridin-4-yl)methylamine (hydrochloride salt) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].F[C:11]1[C:16]([C:17]#[N:18])=[C:15]([F:19])[C:14]([C:20]#[N:21])=[C:13]([F:22])[C:12]=1[F:23].[F-].[K+]>C(#N)C.CC(C)=O.C1CCCCC1>[F:19][C:15]1[C:14]([C:20]#[N:21])=[C:13]([F:22])[C:12]([F:23])=[C:11]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: Cc1cccc(C)c1O
Agent: [F-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CC#N
Solvent: CC(C)=O
Product: Cc1cccc(C)c1Oc1c(F)c(F)c(C#N)c(F)c1C#N
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A solution of 1.2 g (10×10-3 mol) of 2,6-dimethylphenol in 40 ml of acetonitrile was dropwise added at a temperature of -10° C. to a solution of 2.0 g (10×10-3 mol) of tetrafluoroisophthalonitrile and 2.9 g (50×10-3 mol) of potassium fluoride. The mixture was allowed to stand at a temperature of -10° C. to 0° C. for 1 hour while stirring and the undissolved potassium fluoride was separated by filtration. The filtrate was concentrated to dryness in vacuo. The resultant residue was dissolved in a mixed solvent of acetone and cyclohexane and 2.3 g (77% yield) of the desired compound No. 37 was obtained as white crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[C:16]([Si:19]([CH3:21])([CH3:20])[O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH2:1])([CH3:18])([CH3:17])[CH3:15]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 2-amino-5-methyl-phenol (500 mg, 4.0 mmol) and imidazole (298 mg, 4.4 mmol) in DMF (5 ml) was added TBDMSCl (660 mg, 4.4 mmol). The reaction mixture was stirred at RT for 3 h then diluted into water and extracted with AcOEt. The organic fraction was dried over Na2SO4, filtered and evaporated to dryness. The resulting residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME containing 5% of 7M NH3 in MeOH 95:5→8:2) to yield the title compound (724 mg, 3.1 mmol, 77%) as a redish oil. TLC: RF=0.94 (heptane/DCM/TBME 1:1:2 containing 5% of 7M NH3 in MeOH); HPLC: AtRet=1.80 min; API-MS: m/z 238.1 [M+H]+; 1H NMR (400 MHz, CDCl3): 0.26 (s, 6H), 1.04 (s, 9H), 2.23 (s, 3H), 3.56 (br. s., 1H), 6.56-6.67 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55]([F:57])([F:56])[F:58])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C1) (124 mg, 1.2 equiv), ethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}propanoate (Int. B3) (139 mg, 1 equiv), DMF (1.2 ml) and DIPEA (0.16 ml, 3 equiv) was shaken at room temperature for 30 min, then HATU (176 mg, 1.5 equiv) was added and shaking continued for 4 h. Reverse phase HPLC (Preparative Method B) gave ethyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}-2-methylpropanoate as a white solid (174 mg).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([CH3:19])=[C:14]([CH2:20][O:21][CH3:22])[N:13]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH3:22][O:21][CH2:20][C:14]1[N:13]=[C:12]([Cl:11])[N:17]=[C:16]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[C:15]=1[CH3:19]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COCc1nc(Cl)nc(Cl)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
1,2,3,4-tetrahydroisoquinoline(0.9 ml, 6.9 mmol) was added dropwise to a solution of 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3 mmol) and triethylamine(0.96 ml, 6.9 mmol) in dimethylformamide and stirred for 5 hours at a room temperature. The reaction mixture was diluted with dichloromethane and washed with water and aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to give 1.8 g of the titled compound. (Yield: 94.0%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][C:13]([CH3:24])=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.Cl.[BH4-].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a suspension of 5.0 g (15.5 mmol) of the known 1-(4-nitrophenyl-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (French patent specification No. 85,09793) in 380 ml of ethanol first 22.5 ml (0.278 mol) of concentrated hydrochloric acid were added at constant stirring whereupon a solution was formed within a few minutes, then 11.5 g (0.3 mole) of sodium borohydride were charged into the solution portionwise during 30 minutes. Stirring was continued for 15 minutes, then the orange-coloured precipitate formed was filtered and extracted on the filter with 4×30 ml of chloroform. The combined chloroform filtrate was evaporated under reduced pressure, the crystalline residue was brought to a filter with 200 ml of distilled water, then washed with 3×20 ml of distilled Water and dried at 80°-100° C. to yield 4.90 g (97.2%) of the aimed product, m.p.: 162°-164° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C@@H:2]([CH2:11][O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](N)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1S,2S)-2-amino-1-phenyl-1,3-propanediol (2.07 g, 12.4 mmol) in DMF (10 mL) was added imidazole (1.0 g, 14.7 mmol) and tert-butyldimethylsilyl chloride (2.30 g, 15.3 mmol). After stirring at rt for 12 h the mixture was added to diluted brine (150 mL, water/brine:1/1). Extraction with ethyl acetate (4×30 mL), washing of the combined extracts with brine (30 mL) and drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: ethyl acetate). The title compound was obtained as colourless oil. δH (CDCl3): 0.24, 0.26 (6H, 2s), 1.12 (9H, s), 2.50–2.78 (3H, br s), 3.16 (1H, ddd), 3.78 (1H, dd), 3.85 (1H, dd), 4.84 (1H, d), 7.49–7.55 (5H, m); m/z (ES+)=282.32 [M+H]+; RT=2.87 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([Br:24])[C:21]=1[O:22][CH3:23])[C:16](Cl)=[O:17].C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:16]([C:15]3[CH:19]=[C:20]([Br:24])[C:21]([O:22][CH3:23])=[C:13]([Br:12])[CH:14]=3)=[O:17])[C:4]=2[CH:3]=1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: Brc1cnc2c(c1)NCCO2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(Br)cc32)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a 10 ml flask, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (37 mg, 0.172 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (113 mg, 0.344 mmol) were dissolved in dichloromethane (0.5 ml). Triethylamine (0.120 ml, 0.860 mmol) was added thereto and then stirred at room temperature for 1 hour. After completion of the reaction by adding water to the reaction mixture, the organic layer was extracted with dichloromethane and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:ethyl acetate:n-hexane=1:2:5. The fractions containing the product were collected and evaporated to obtain white solid (55 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](Cl)=[N:6][S:5][N:4]=1.CS(C)=O.[S:13]([NH2:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>O>[CH3:1][O:2][C:3]1[C:7]([NH:23][S:13]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)(=[O:14])=[O:22])=[N:6][S:5][N:4]=1
Reactant: COc1nsnc1Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1nsnc1NS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.7 %

Procedure:
150.6 g of 3-methoxy-4-chloro-1,2,5-thiadiazole (1 mole) were suspended in 156.26 g of dimethyl sulfoxide (2 mole) and 258.31 g of sulfanilamide (1.5 mole) and 414.63 g of potassium carbonate (3 mole) were then added. The mixture was kept at 70° C. for 48 hours while stirring. 600 ml of water were then added, the mixture was cooled to ambient temperature and adjusted to pH 1.5 with concentrated hydrochloric acid. The precipitated crystallized material was filtered off, washed with water and dried. A yield of 271.1 g of crude 3-methoxy-4-(4'-aminobenzenesulfonamido)-1,2,5-thiadiazole (94.67% of theory), melting point 138°-146° C., was obtained.