Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC>C(Cl)Cl>[CH3:3][O:4][C:5]([C:6]1[N:15]=[C:16]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[O:26][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:27]
Reactant: COC(=O)C(NC(=O)CNC(=O)OC(C)(C)C)C(O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: II
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nc(CNC(=O)OC(C)(C)C)oc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(2-tert-butoxycarbonylamino-acetylamino)-3-hydroxy-3-phenyl-propionic acid methyl ester (620 mg, 1.76 mmol) in CH2Cl2 (20.0 mL) was treated at 0° C. with Dess-Martin periodinane (923 mg, 2.11 mmol). The resulting mixture was stirred at rt for 1 h and filtered through a short plug of basic alumina (activity I) and sand into a flask containing a freshly prepared solution of triphenylphosphine (946 mg, 3.55 mmol), I2 (902 mg, 3.52 mmol) and Et3N (0.98 ml, 7.04 mmol) in CH2Cl2 (22.0 mL). The filter cake was washed with CH2Cl2. After 15 min, the reaction mixture was transferred to a separatory funnel, treated with sat. aq. Na2S2O3 (150 mL) and extracted with CH2Cl2 (2×150 mL). The organic layer was washed with sat. aq. NaHCO3 (150 mL), filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (50:50 CH2Cl2-MeOH) gave the title compound as a white solid. TLC: rf (50:50 CH2Cl2-MeOH)=0.33. LC-MS-conditions 02: tR=0.99 min, [M+H]+=333.39.
Reaction SMILES: N#N.[C:3]([O:15]C)(=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[C:21]([OH:39])[C:20]=1[O:40][CH3:41].C([Sn](=O)CCCC)CCC>CO>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:30][CH2:31]2)=[C:21]([OH:39])[C:20]=1[O:40][CH3:41].[C:3]([O-:15])(=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: CCCC[Sn](=O)CCCC
Agent: COc1ccc(CN2CCN(Cc3ccccc3)CC2)c(O)c1OC
Agent: N#N
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
Into a 4-necked, 1-liter flask fitted with a mechanical thermometer, N2 ebulator, and steam jacketed column packed with Berl Saddles and topped with a Dean-Stark trap and condenser are charged dimethyl terephthalate (220 grams, 1.14 moles), BHDP (300 grams, 1.36 moles) and dibutyltin oxide (1.4 grams). The mixture is heated at 180°-190° C. for 5.5 hours. A conversion of 94 percent is effected based upon methanol distilled overhead. The solid yellow glass (viscosity 40,000 cp at 220° F.) has an average molecular weight of 2,060, an acid member of 1.2, and a hydroxyl number of 51.3.
Reaction SMILES: O.[OH-].[Li+].[Si:4]([O:11][CH2:12][CH:13]([CH2:20][CH:21]=[CH2:22])/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>O1CCCC1.CO.O>[Si:4]([O:11][CH2:12][CH:13]([CH2:20][CH:21]=[CH2:22])/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[CH3:6]
Reactant: C=CCC(/C=C/C(=O)OC)CO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCC(/C=C/C(=O)O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Lithium hydroxide monohydrate (2.52 g, 60.0 mmol) was added to a tetrahydrofuran:methanol:water (3:1:1, 100 mL) mixed solution of methyl (2E)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)hepta-2,6-dienoate (5.69 g, 20.0 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure. To the residue, water was then added, followed by extraction with methylene chloride. The aqueous layer was made acidic by the addition of 10% hydrochloric acid, followed by extraction with methylene chloride again. Then, the combined organic layers were dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (3.11 g, 57%).
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=[CH:4][CH:5]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2ccnn2O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: COc1ccc(-c2ccnn2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-5-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (38%, yellow crystals).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>COCCOC>[CH2:18]([O:17][C:15]([C:14]1[N:1]=[C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][N:3]2[CH:13]=1)=[O:16])[CH3:19]
Reactant: Nc1cnc(C(F)(F)F)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cn2cc(C(F)(F)F)ncc2n1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-5-(trifluoromethyl)pyrazine (500 mg, 3.07 mmol) in 1,2-dimethoxyethane (10 mL) was added dropwise ethyl bromopyruvate (0.5 mL, 4.0 mmol). The reaction mixture was warmed to 60° C. for 72 hours. The reaction mixture was then cooled to room temperature, and water was added (10 mL) to precipitate a solid. The suspension was stirred for 10 minutes, filtered, and the isolated solid was washed with water to afford the desired ester which was used in the next step without further drying. 1H NMR (CDCl3) δ 9.22 (s, 1H), 8.59 (s, 1H), 8.39 (s, 1H), 4.50 (q, 2H), 1.47 (t, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:26][O:27][NH:28][CH3:29].O>C1COCC1>[CH3:26][O:27][N:28]([CH3:29])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred brown solution of 1H-indole-6-carboxylic acid (2.68 g, 16.6 mmol) in THF (25 mL) was added CDI (2.97 g, 18.3 mmol) and stirred at room temperature for 2 hours. The mixture was then cooled to 0° C. and O,N-dimethyl-hydroxylamine hydrochloride (1.95 g, 20.0 mmol) was added and stirred at room temperature over night. Water (50 mL) was added to the reaction and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give 1H-indole-6-carboxylic acid methoxy-methyl-amide as an oil (3.87 g, 114% crude yield): 1H NMR (CDCl3) 3.40 (s, 3H, NCH3), 3.59 (s, 3H, OCH3), 6.57-6.59 (m, 1H, Ar), 7.31-7.33 (m, 1H, Ar), 7.46-7.50 (m, 1H, Ar), 7.64 (d, J=8 Hz, 1H, Ar), 7.84 (s, 1H, Ar), 8.60 (brs, 1H, NH). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:3][C:2]([CH3:19])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][N:16]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: O=C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C3CCCCC3)CC2)CC1
Yield: 99 %

Procedure:
Prepared analogously to Example A19a) from 1-(1,1-dimethylethoxycarbonyl)-4-(4-piperidinyl)piperazine and cyclohexanone in a yield of 99% of theory. Colourless, highly viscous oil.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([OH:37])[CH2:36][O:35][CH2:34]2)[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([C:33]4([OH:37])[CH2:36][O:35][CH2:34]4)=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)COC3)cc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(O)COC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(3-hydroxyoxetan-3-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 193. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.30 (dd, J=8.7, 4.0 Hz, 1H), 8.23-8.12 (m, 1H), 7.90 (s, 1H), 7.49 (d, J=9.7 Hz, 2H), 4.81 (t, J=5.7 Hz, 3H), 4.73 (dd, J=7.0, 1.4 Hz, 2H), 4.41-4.17 (m, 1H), 4.10-3.87 (m, 2H), 3.76 (s, 3H), 3.19-3.09 (m, 1H), 2.11-2.02 (m, 1H), 1.69 (s, 3H). LCMS (ES+) m/z 536 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[C:11]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:25][CH:26]([O:29][C:30](=[O:32])[CH3:31])[CH:27]=[CH2:28])(=[O:24])[CH3:23].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:28]=[CH:27][CH:26]([O:25][C:22](=[O:24])[CH3:23])[O:29][C:30](=[O:32])[CH3:31])[CH:16]=3)[C:11]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(OC(C)=O)OC(C)=O
Reactant: O=C1c2ccc(Br)cc2CCN1CCCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC(C=Cc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O)OC(C)=O
Temperature: 25 °C

Procedure:
To a sealed tube apparatus is added 2-(3-phenylpropyl)-6-bromo-1-oxo-1,2,3,4tetrahydroisoquinoline (1.6 g, 4.65 mmol), CH3CN (8 mL), 1,1-diacetoxy-2-propene (3.4 mL, 23.25 mmol), Pd(OAc)2 (84 mg, 0.37 mmol), P(o-tolyl)3 (113 mg, 0.37 mmol) and Et3N (0.78 mL, 5.58 mmol). The reation vessel is then sealed and the mixture heated to 120° for 48 hours. After cooling to ambient temperature the reaction mixture is diluted with EtOAc (150 mL) and filtered through Celite. The organic phase is washed with saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 9:1 hexane/EtOAc, 1:1 hexane/EtOAc, 1:1 hexane/EtOAc) to give 2-(3-phenyl-propyl)-6-(3,3-diacetoxy-1-propen-1-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C:13]([F:16])([F:15])[CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:16][C:13]1([F:15])[CH2:12][NH:11][C@@H:10]([C:5]2[CH:4]=[C:3]([CH:8]=[C:7]([F:9])[CH:6]=2)[C:1]#[N:2])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@H]1c1cc(F)cc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(F)cc([C@H]2CC(F)(F)CN2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4,4-difluoropyrrolidine-1-carboxylate (I-23) (0.45 g, 1.4 mmol) in DCM (3 mL) was added TFA (3 mL) and stirred at room temperature for 1 hour. All the solvents were removed under reduced pressure. The crude was diluted with EtOAc, washed with aqueous NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated to yield (R)-3-(4,4-difluoropyrrolidin-2-yl)-5-fluorobenzonitrile (I-24) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1 H), 7.42 (d, J=9.2 Hz, 1 H), 7.29-7.26 (m, 1 H), 4.46 (t, J=8.8 Hz, 1 H), 3.52-3.30 (m, 2 H), 2.74-2.60 (m, 1 H), 2.20-2.04 (m, 1 H), 1.90 (bs, 1 H). MS m/z 227.1 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](I)[CH2:13][CH3:14].[OH-].[K+].C>C(O)C.O>[CH2:12]([O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:1])[CH2:13][CH3:14]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOc1cccc(C(=O)O)c1O
Yield: 65 %

Procedure:
2,3-Dihydroxybenzoic acid (6.16 g) and propyl iodide (6.8 g) were added to a mixture of aqueous potassium hydroxide solution (20 ml, 25% w/v), water (50 ml) and ethanol (50 ml) and the mixture was stirred and heated at reflux for 5 hours. A further quantity of propyl iodide (17 g) was then added and the mixture was again heated at reflux for 4 hours, small quantities of solid potassium hydroxide being added meanwhile in order to keep the pH at about 10. Decolourizing charcoal was then carefully added, the mixture was filtered hot and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid. The resulting solid was filtered off and dissolved in aqueous ammonia solution (2N), and the solution was treated with decolourizing charcoal, filtered, and the filtrate was acidified to pH 1 by treatment with hydrochloric acid to give 3-propoxysalicylic acid (5.1 g), m.p. 114°-118° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)cc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)cc(OCC(F)(F)F)n2)cc1
Temperature: 120 °C
Yield: 78.6 %

Procedure:
To a solution of tert-butyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (30 mg, 0.07 mmol), and Hunig's Base (0.026 mL, 0.15 mmol) in THF (1 mL) was added 4-(aminomethyl)phenol (33 mg, 0.27 mmol). The resulting mixture was stirred at 120° C. for 30 hs. The solvent was removed and the crude product was purified by silica gel chromatography using 20% -40% of EtOAc/Hexanes to give tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (27 mg, 74%) as white solid.
Reaction SMILES: C([O:5][P:6]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])CCC.Cl[C:18]([O:20][CH3:21])=[O:19]>>[CH3:21][O:20][C:18]([P:6](=[O:5])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19]
Reactant: COC(=O)Cl
Reactant: CCCCOP(OCCCC)OCCCC
Product: CCCCOP(=O)(OCCCC)C(=O)OC

Procedure:
From 26.6 g (0.10 mole) of tri-n-butylphosphite and 18.9 g (0.20 mole) of methyl chloroformate (80° C., 6 hours). Yield 22.4 g (89%). Bp0.2 85°-105° C., nD25 1.4310.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](CC(N3CCOCC3)=S)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:20][C:19]([OH:22])=[O:21])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: S=C(Cc1ccc2c(c1)CCO2)N1CCOCC1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCO2

Procedure:
2,3-dihydrobenzofuran-5-ylthioacetic acid morpholide (5.0 g) was heated at reflux in a solution of acetic acid (20 ml), concentrated sulfuric acid (3.0 ml) and water (4.5 ml). After 3 hours the reaction mixture was cooled and added to water. The product was extracted with ethyl acetate and the combined extracts washed five times with water. The organic solution was then extracted with aqueous saturated sodium bicarbonate solution. The aqueous solution was then acidified and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to give a residue which was recrystallized from acetone/hexane to give 2,3-dihydrobenzofuran-5-ylacetic acid, m.p.--96°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=O)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)[CH3:32]>CN(C1C=CN=CC=1)C>[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:20])[CH:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:37][CH:36]=1)[CH3:32]
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-benzoic acid ethyl ester (CAS Reg. No. 94-09-7]) in the presence of DMAP to give the title compound as colorless oil. MS: m/e=516.4 [M+H+].
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:13])[C:7]2[S:12][CH2:11][CH2:10][C:8]=2[N:9]=1)C.Cl.CC(O)=[O:17]>O>[NH:9]1[C:8]2[CH2:10][CH2:11][S:12][C:7]=2[C:6](=[O:13])[NH:5][C:4]1=[O:17]
Reactant: CCSc1nc2c(c(=O)[nH]1)SCC2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2c(c(=O)[nH]1)SCC2
Temperature: 110 °C
Yield: 82 %

Procedure:
To a suspension of 2-(ethylthio)-6,7-dihydrothieno[3,2-d]pyrimidin-4(3H)-one (2.80 g, 13.06 mmol) in water (2.0 mL) was added 2.0 mL of conc. HCl and 4.0 mL of AcOH. The mixture was heated at 110° C. overnight. The reaction was cooled and the solid that formed collected by filtration washed with water and methanol, and dried to afford a white solid, 6,7-dihydrothieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, (1.80 g, 82%). Without further purification, the crude product was used directly to the next step.
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].[S:12]([O:16]C)([O:14]C)=[O:13]>>[CH3:2][S:12]([O-:16])(=[O:14])=[O:13].[CH2:2]([N+:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: COS(=O)OC
Agent: CCCC[N+]1(C)CCCC1
Agent: [Cl-]
Product: CS(=O)(=O)[O-]
Temperature: 112.5 °C
Reaction time: 48 h

Procedure:
A mixture of 11.20 g (63.0 mmol) of 1-butyl-1-methylpyrrolidinium chloride and 13.0 g (118.0 mmol) of dimethyl sulfite is stirred at 110-115° C. (temperature of the oil bath) for 48 hours under an inert-gas atmosphere (nitrogen) in a sealed reaction vessel with pressure valve for 1-1.5 bar above atmospheric pressure. The end of the reaction is determined by NMR measurement. The product is pumped off over the course of 5 hours in vacuo at 13.3 Pa and 115° C. (temperature of the oil bath), giving 14.9 g of 1-butyl-1-methylpyrrolidinium methanesulfonate as a solid. The melting point is 59-60° C. The residual chloride content is less than 5 ppm. The yield is virtually quantitative. The product is investigated by means of NMR spectroscopy.
Reaction SMILES: [CH2:1]([C:3]1([CH2:12][CH:13]=[CH2:14])[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11])[CH3:2].[BrH:15]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:12][CH2:13][CH2:14][Br:15])[C:4](=[O:11])[NH:5][C:6](=[O:10])[NH:7][C:8]1=[O:9])[CH3:2]
Reactant: Br
Reactant: C=CCC1(CC)C(=O)NC(=O)NC1=O
Solvent: Cc1ccccc1
Product: CCC1(CCCBr)C(=O)NC(=O)NC1=O
Reaction time: 8 h

Procedure:
A suspension of 40 g of 5-ethyl-5-allylbarbituric acid and 800 ml of toluene was stirred and irradiated with a GE sunlamp (275 watts, 110-125 volts) for approximately 90 min. Thereafter, gaseous HBr was passed for 45 min. with further irradiation and stirred for another 45 minutes. The reaction flask was then opened to allow the excess HBr to evaporate. The solution was cooled and filtered. The resulting precipitate was washed with toluene, dried, and then dissolved in a minimal amount of hot acetone. Petroleum ether (60°-68° C.) was added until a small amount of precipitate appeared; the flask was left overnight at 23° C. The crystals were filtered, washed with petroleum ether, and air dried. The melting point was 138°-140° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[OH:11][CH2:12][CH2:13][O:14][C:15]1[C:20]2[N:21]=[C:22]([NH2:24])[O:23][C:19]=2[CH:18]=[CH:17][CH:16]=1>>[Cl:10][C:9]1[C:4]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]3[N:21]=[C:22]([NH2:24])[O:23][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccnc1Cl
Reactant: Nc1nc2c(OCCO)cccc2o1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc2c(OCCOc3nccnc3Cl)cccc2o1

Procedure:
The title compound was prepared according to the procedure of Example 4, Step 1, except that 4 equiv of both NaH and 2,3-dichloropyrazine were used, starting from the product of Step 1. The reaction temperature was 90° C. The crude product was used directly in the next step.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)C1C=CC=CC=1>[Pd].CCO>[C:21]([O:20][C:18](=[O:19])[NH:17][C@H:14]1[CH2:13][CH2:12][C@@H:11]([NH2:10])[CH2:16][CH2:15]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1

Procedure:
Cbz BOC diamine (294) (458 mg, 1.05 mmol) (containing residual benzyl alcohol) and 10% palladium on charcoal (92 mg, 20% by weight) in EtOH (9 mL) was stirred under a hydrogen atmosphere until the reaction was complete. The reaction was filtered through celite, washed with more EtOH and reduced in vacuo to give the title compound.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[O:14]1[CH2:5][CH2:4][N:3]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:6]2[CH:7]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCCCBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCCCBr)N1CCOc2ccccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b]oxazine (500 mg, 1 eq, 3.7 mmol), triethylamine (1.54. ml, 3 eq, 11.1 mmol) and catalytic amount of DMAP in dry DCM (20 ml) was added 5-bromo pentanoyl chloride (870 μl, 2 eq, 7.40 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 4 h and then diluted with excess ethyl acetate. The ethyl acetate layer was washed with dil. HCl, water and then with brine. The residue was chromatographed with ethyl acetate and hexane to yield the title compound liquid (535 mg, yield 53%) as viscous liquid.