Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:18])=[CH:6][C:7]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=2.[CH2:19]([Sn](CCCC)(CCCC)C=C)[CH2:20]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:5]1[N:4]=[N:3][C:2]([CH:19]=[CH2:20])=[C:7]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[CH:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cccc2[nH]c(-c3cc(Cl)nnc3Cl)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1nnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 30.1 %

Procedure:
To a degassed solution of 2-(3,6-dichloropyridazin-4-yl)-4-fluoro-1H-indole (500 mg, 1.7 mmol), tributyl(vinyl)stannane (560 mg, 1.7 mmol) and LiCl (375 mg, 8.9 mmol) in DMF (5 mL) was added Pd(PPh3)2Cl2 (30 mg) under N2, and the mixture was stirred at 80° C. for 12 h. After the solvent was removed, the residue was purified by prep-TLC (PE:EtOAc=2:1) to give the product of 2-(6-chloro-3-vinylpyridazin-4-yl)-4-fluoro-1H-indole (140 mg, yield: 29%). 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 7.61 (s, 1H), 7.16 (dd, J=10.8, 16.8 Hz, 2H), 7.03 (s, 1H), 6.87 (d, J=6.8 Hz, 2H), 6.68 (s, 1H), 5.79 (s, 1H). MS (M+H)+: 274/276.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[C:29]3[C:28]4[N:30]=[CH:31][CH:32]=[CH:33][C:27]=4[CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][CH:21]=2)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[C:29]3[C:28]4[N:30]=[CH:31][CH:32]=[CH:33][C:27]=4[CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][CH:21]=2)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C(Nc1cccnc1OCCOC1CCCCO1)c1c[nH]c2c1-c1ncccc1CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(Nc1cccnc1OCCO)c1c[nH]c2c1-c1ncccc1CCC2
Yield: 101.4 %

Procedure:
A solution of 3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acid {2-[2-(tetrahydropyran-2-yloxy)-ethoxy]-pyridin-3-yl}amide (850 mg) and p-toluenesulfonic acid monohydrate (700 mg) in methanol (30 mL) is refluxed for 1 h. The solvent is removed and the residue is extracted with DCM and washed with NaHCO3 (aq.). The organic layer is dried and solvent removed to give 700 mg of 3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid [2-(2-hydroxy-ethoxy)pyridin-3-yl]amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[S:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1.I([O-])(=O)(=O)=[O:39].[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[S:12](=[O:39])[CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1cc2c(cc1OC)SCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)S(=O)CCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Reaction time: 48 h
Yield: 78.9 %

Procedure:
In methanol (10 ml) is dissolved 1-(7,8-dimethoxy-2,3-dihydro-1-benzothiepin-4-carbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.6 g) obtained in Working Example 24. To the solution is added dropwise, while stirring under ice-cooling, a solution of sodium periodate (960 mg) in water (1 ml). The mixture is stirred for one hour under ice-cooling, and left standing for 48 hours at -5° C. Resultant precipitates are filtered off. To the filtrate is added water, followed by extraction with methylene chloride. The organic layer is washed with an aqueous solution of sodium hydrogencarbonate, dried, and concentrated under reduced pressure. The residue is recrystallized from ethanol-ether to give 1-(7,8-dimethoxy-1-oxo-2,3-dihydro1-benzothiepin-4-carbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine as colorless prisms (1.3 g), m.p. 138° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.O>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Br
Solvent: O
Product: O=C1CCCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
6-Methoxy-1-tetralone (80 g, 453 mmol) was taken up in 48% HBr (270 ml) at 4° C., then stirred at ambient temperature for 4 hr. Distilled H2O (1 l) was added with cooling to 4° C. and the precipitated solid was filtered, washed with H2O and recrystallised twice from EtOH-H2O (4:1) to afford 6-hydroxy-1-tetralone as a beige solid (59.7g, 368 mmol, 81%), Mp. 153-155° C., MS m/e=162.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH:22]([CH3:26])[C:23](=O)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH3:24])[CH:22]([Cl:21])[CH3:26])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CC(=O)C(C)Cl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(C)Cl

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with 3-chloro-2-butanone to give 7-chloro-2-[(2-chloro-1-methylpropylidene) hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH2:23]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O)[CH2:24][CH2:25][CH3:26].[O-]CC.[Na+]>C(O)C>[CH2:23]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1/[CH:30]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=1)[CH2:24][CH2:25][CH3:26]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: CCCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)cccc1OC
Yield: 44.4 %

Procedure:
The title compound was synthesized by the condensation of Intermediate 15 (400 mg, 1.225 mmol) with 2-butoxy-3-methoxybenzaldehyde (337 mg, 1.716 mmol) in presence of sodium ethoxide (166 mg, 2.457 mmol) in ethanol (25 ml) according to the procedure described in Example 24 to give 281 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=6.9 Hz, 3H), 1.40-1.52 (m, 4H), 3.77 (s, 3H), 3.80-3.90 (m, 2H), 6.80-6.90 (m, 2H), 6.98-7.05 (m, 2H), 7.40-7.46 (m, 4H), 7.50 (d, J=4.8 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 8.07 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 517.15 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13](O)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>[OH-].[Na+]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]1[S:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)CCc1cnc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2nc(CCc3nc4ccccc4s3)cnc2c1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(quinoxalin-2-yl)propanoic acid (530 mg, 2.6 mmol) and 2-aminobenzenethiol (390 mg, 3.12 mmol) in PPA (7 g) was heated to 120° C. and stirred for 10 minutes. The reaction mixture was cooled and aqueous NaOH (20 mL) was added. The mixture was extracted with DCM (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated and then purified by prep-TLC to give 2-(2-(quinoxalin-2-yl)ethyl)benzo[d]thiazole as a yellow solid. (38 mg). MS (ESI) m/z 318 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([OH:15])CO)[C:8]([C@@H:16]([N:18]1[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]1=[O:28])[CH3:17])=[CH:7]2.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:15])[C:8]([C@@H:16]([N:18]1[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]1=[O:28])[CH3:17])=[CH:7]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1C(O)CO)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1cc2cccc(Cl)c2nc1C=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-((S)-1-(8-chloro-2-(1,2-dihydroxyethyl)quinolin-3-yl)-ethyl)isoindoline-1,3-dione (170 mg, 0.43 mmol) in THF (4.0 mL) and water (1.0 mL) was added sodium periodate (91.6 mg, 0.43 mmol). The reaction was stirred at room temperature for 3 hours and then it was diluted with water (50 mL). The separated aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated in vacuo to give (S)-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-quinoline-2-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ ppm 10.36 (1H, s), 8.59 (1H, s), 7.89-7.91 (1H, m), 7.82-7.86 (3H, m), 7.71-7.73 (2H, m), 7.57-7.61 (1H, m), 6.67 (1H, q, J=7.0 Hz), 2.00 (3 H, d, J=7.0 Hz).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:14][C:15]1[CH:20]=[C:19]([N:21]=[C:22]=[O:23])[CH:18]=[C:17]([Cl:24])[N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([NH:21][C:22]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:23])[CH:18]=[C:17]([Cl:24])[N:16]=1
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Reactant: Cc1cc(NN)nc2ccccc12
Product: Cc1cc(NNC(=O)Nc2cc(Cl)nc(Cl)c2)nc2ccccc12

Procedure:
A solution of 2-hydrazinyl-4-methylquinoline (100 mg, 0.58 mmol) and 110 mg (1.0 eq) of 2,6-dichloro-4-isocyanatopyridine was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.57 (s, 3 H) 6.80 (s, 1 H) 7.30 (t, J=7.47 Hz, 1 H) 7.50-7.64 (m, 2 H) 7.87 (d, J=8.20 Hz, 1 H) 8.78 (s, 1 H) 8.91 (br. s., 1 H).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[C@@H:12]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C@H:11](O)[CH2:10]2.[CH2:23]([N:25](CC)CC)C.CN>O1CCCC1.C(O)C>[Cl:16][C:15]1[CH:14]=[C:10]2[C:9](=[CH:8][C:7]=1[Cl:6])[C@@H:13]([NH:25][CH3:23])[C@H:12]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:11]2
Reactant: O[C@@H]1Cc2cc(Cl)c(Cl)cc2[C@H]1N1CCCC1
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN[C@@H]1c2cc(Cl)c(Cl)cc2C[C@H]1N1CCCC1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 17 ml of methane sulfonyl chloride in 3 ml of tetrahydrofuran was added dropwise at -20° C. to a mixture of 5 g of the product of Step E, 40 ml of tetrahydrofuran and 4 ml of triethylamine and after stirring for 15 minutes at -20° C., the temperature was raised to 0° C. and 20 ml of methylamine in ethanol were added. The mixture was stirred for 22 hours and was evaporated to dryness. The residue was diluted with water and after the addition of a few drops of sodium hydroxide solution, the mixture was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 5.7 g of residue. The latter was chromatographed on silica and eluted with a 8-1-1 ethyl acetate-methanol-triethylamine mixture and after standing at 4° C., 4.91 g of the desired crystalline product melting at ≈55° C. were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>>[NH2:19][CH:20]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:21]1
Reactant: NC1CCNC1
Reactant: Clc1ccccc1OCCOc1nccnc1Cl
Product: NC1CCN(c2nccnc2OCCOc2ccccc2Cl)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and 3-aminopyrrolidine (252 mg, 2.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 100 mg (56%) of the title product. Anal. (C16H19ClN4O2) C, H; N: calcd, 16.73; found, 16.0.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8](C)[C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([O-:13])=O)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:18]([N:20]([CH2:23][CH2:24][NH2:25])[CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:21][CH3:22])[CH2:23][CH2:24][NH:25][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]=1[O:15][CH3:16])[CH3:19]
Reactant: CCN(CC)CCN
Reactant: CCCC(=O)c1cc(C)c(OC)c(C(=O)[O-])c1
Product: CCCC(=O)c1ccc(OC)c(C(=O)NCCN(CC)CC)c1
Temperature: 100 °C

Procedure:
In a flask equipped with a Dean-Stark device, there are introduced 10 g of the ester obtained in Example 3 and 10 g of diethylaminoethylamine and the mixture is heated to 100° C. for 3 hours. There are thus obtained 10.3 g of an oily product which is converted to hydrochlorate in the ethanol-ether mixture. The product obtained has a melting point of 155° C.
Reaction SMILES: [C:1]([O-:15])(=O)[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2].[C:17]([O-:31])(=O)[CH2:18][CH2:19][NH:20][C:21](=[O:29])[C@@H:22]([C:24]([CH2:27][OH:28])([CH3:26])[CH3:25])[OH:23].Cl.Cl.[NH2:34][CH2:35][CH2:36][S:37][S:38][CH2:39][CH2:40][NH2:41].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.O>[CH3:26][C:24]([C@@H:22]([OH:23])[C:21]([NH:20][CH2:19][CH2:18][C:17]([NH:34][CH2:35][CH2:36][S:37][S:38][CH2:39][CH2:40][NH:41][C:1]([CH2:2][CH2:3][NH:4][C:5]([C@H:6]([OH:7])[C:8]([CH2:11][OH:12])([CH3:9])[CH3:10])=[O:13])=[O:15])=[O:31])=[O:29])([CH2:27][OH:28])[CH3:25]
Reactant: NCCSSCCN
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Ca+2]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO
Reaction time: 1 h
Yield: 69.2 %

Procedure:
11.9g. of calcium pantothenate, 6.8g. of cystamine dihydrochloride and 7.7g. of 1-hydroxylbenzotrizole were dissolved in 50ml. of pyridine and 10ml. of water, and thereafter pyridine (25ml.) solution of 10.5g. of dicyclohexylcarbodiimide was added thereto at a time, and the reaction was effected at a temperature below 10° C for 1 hour and then for 5 hours at a room temperature. Next the solvent was removed under a reduced pressure, the residue thereof was added with 50ml. of water, and the deposited crystals were removed by filtration. Pyridine left in the filtered mother liquor was completely removed azetropically with water. The residue thereof was added with 50ml. of water and after cooling, the deposited crystals were filtration removed and extracted with 20ml. of chloroform two times. The water layer was treated under a reduced pressure to remove the remaining chloroform, and thereafter like Example 1, passed through the ion exchange resin, and the flowed out liquid was concentrated under a reduced pressure and thereby colorless transparent viscous liquid of pantethine which was the objective compound was obtained. Drying was carried out by means of a vacuum dryer for one night and as a result 9.6g. of pantethine (yield rate 69.2%) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Br[CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]>C1COCC1.O>[CH3:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:6][CH2:3][C:4]#[CH:5]
Reactant: COCCOCCBr
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCCOCCOC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
To a stirred suspension of sodium hydride (3.12 g, 78.0 mmol) in THF (100 mL) cooled to 5° C. in an ice-bath was added a solution of propargyl alcohol (4.60 g, 78.0 mmol) in THF (20 mL) drop-wise. The mixture was stirred at 5° C. for 30 min and was then allowed to warm to RT and treated dropwise with 1-bromo-2-(2-methoxyethoxy)ethane (7.00 mL, 52.0 mmol). The reaction mixture was stirred at RT for 16 hr and was then, diluted with water (100 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts were dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 30% EtOAc in heptane, to afford the title compound (9) (250 mg, 9%) as a colourless oil: 1H NMR (500 MHz, MeOD) δ: 4.18 (2H, d), 3.66-3.69 (2H, m), 3.60-3.66 (4H, m), 3.52-3.56 (2H, m), 3.36 (3H, s), 2.84 (1H, t).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])=[CH:5][C@H:6]1[CH2:10][NH:9][C:8](=[O:11])[CH2:7]1.[CH3:13][O:14][C:15](=[O:21])[C:16](C)(Br)[CH2:17][CH3:18]>O1CCCC1.O>[CH3:13][O:14][C:15](=[O:21])[CH:16]([N:9]1[CH2:10][C@H:6]([CH:5]=[C:4]([F:12])[F:3])[CH2:7][C:8]1=[O:11])[CH2:17][CH3:18]
Reactant: O=C1C[C@@H](C=C(F)F)CN1
Reactant: CCC(C)(Br)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(=O)OC)N1C[C@H](C=C(F)F)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A slurry of 60% sodium hydride suspension in mineral oil (0.80 g, 20.4 mmol) in tetrahydrofuran (28 mL) is cooled at 0° C. under a nitrogen atmosphere. A solution of substantially optically pure (S)-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one (IIIb) (2 g, 13.6 mmol) in tetrahydrofuran (8 mL) is added over a 30 minutes period. The reaction mixture is stirred 10 minutes at 0° C. then a solution of 2-bromo-butyric acid methyl ester (V) (3.20 g, 17.6 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred at 0° C. for 4.5 h then the reaction mixture is allowed to warm to room temperature and diluted with water (15 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (2×10 mL). The combined organic layers are dried over anhydrous magnesium sulfate and evaporated to afford 3 g (12.1 mmol, 89%) of compound (VIb), as a mixture respectively of epimer (VIba) and epimer (VIbb).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[NH:16][C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[C:26]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:25]([CH3:34])[C:24]4=[O:35])=[CH:18][C:14]=2[C:13](=[O:36])[NH:12]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:30]([NH:29][C:26]1[N:25]([CH3:34])[C:24](=[O:35])[C:23]2[C:28](=[C:19]([C:17]3[NH:16][C:15]4[C@@H:11]([CH2:10][CH2:9][OH:8])[NH:12][C:13](=[O:36])[C:14]=4[CH:18]=3)[CH:20]=[CH:21][CH:22]=2)[N:27]=1)([CH3:32])([CH3:33])[CH3:31]
Reactant: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCOCc3ccccc3)NC4=O)cccc2c1=O
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCO)NC4=O)cccc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51.7 %

Procedure:
To a solution of (R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (503b, 555 mg, 1.14 mmol) in DCM (30 mL) at 0° C. was added boron trichloride (1.0 M in DCM, 1.71 mL, 1.71 mmol) slowly dropwise. The resulting tan suspension was stirred at 0° C. for 5 min, then RT for 15 min. LC-MS indicated only unreacted starting material. The reaction mixture was treated with additional BCl3 solution (0.5 mL) at RT and stirred 10 min. LC-MS indicated product formation. The reaction was cooled to 0° C. in an ice bath and treated with MeOH (ca. 3 mL) and ca. 500 mg of powdered NaHCO3 and stirred for 5 min. The reaction mixture was then treated with silica gel and purified on an ISCO Combiflash RF (40 g Silicycle column, using a gradient of 0-20% MeOH in DCM) affording (R)-2-(tert-butylamino)-8-(6-(2-hydroxyethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrolo-2-yl)-3-methylquinazolin-4(3H)-one (503) (233 mg, 0.589 mmol, 51.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, s), 7.88 (2H, dd, J=7.6, 2.5 Hz), 7.66 (1H, br. s.), 7.18 (1H, t, J=7.7 Hz), 6.72 (1H, d, J=1.4 Hz), 5.93 (1H, s), 4.54 (1H, dd, J=8.8, 3.9 Hz), 3.52-3.83 (6H, m), 1.95-2.09 (1H, m), 1.55-1.67 (1H, m), 1.45-1.54 (9H, s). m/z (ESI, +ve) 396.0 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CSc1nnc(N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a mixture of 3.9 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 4.2 g of potassium carbonate and 50 ml of ethanol was gradually added 5 g of ethyl bromoacetate under ice cooling. Then, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 200 ml of water followed by extraction with ethyl acetate. After washing with water, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The solid obtained was washed with toluene and dried to obtain 2.7 g of ethyl [(5-amino-1,3,4-thiadiazol-2-yl)thio]acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[CH3:42][CH:43]([NH2:53])[CH2:44][CH2:45][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:53][CH:43]([CH3:42])[CH2:44][CH2:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[O:17])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(N)CCCc1cccnc1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C(=O)NC(C)CCCc3cccnc3)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
A solution of 50 g of 3',4'-dimethyl[1,1'-biphenyl]-4-carboxylic acid in 200 mL of DMF was cooled in an ice bath and 5.2 mL of diphenylphosphoryl azide was added. After 20 minutes, 3.9 mL of triethylamine was added, and after a further hour, 4.0 g of rac. alpha-methyl-3-pyridinebutanamine was added and the mixture was allowed to warm to room temperature over night. The solvent was evaporated, the residue was taken up in dichloromethane and washed with water and bicarbonate, dried (MgSO4), and purified by preparative hPlc eluting with 95:5 dichloromethane-methanol to give 4.1 g (65%) of rac.-3',4'-dimethyl-N-[1-methyl-4-(3-pyridinyl)butyl][1,1'-biphenyl]4-carboxamide, mp 118°-120° C. after recrystallization from ethyl acetate-hexane. The analytical sample was obtained from ethyl acetate. mp 120°-121° C.