Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([CH2:5][C:6]([NH2:8])=[S:7])#[N:4].Br[CH2:10][C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13].O>C(O)C>[CH3:13][C:12]([C:11]1[N:8]=[C:6]([CH2:5][C:3]#[N:4])[S:7][CH:10]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)CBr
Reactant: N#CCC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1csc(CC#N)n1
Yield: 51.8 %

Procedure:
To a solution of 16.5 g of 85% KOH in 250 ml ethanol was added 25.0 g of 2-cyanothioacetamide. After all of this reagent had dissolved, 44.8 g of bromopinacolone was added dropwise over ca 5 min. The reaction temperature spontaneously climbed to 65° C. and a white solid began to deposit. The mixture was stirred and heated at reflux for 1 hour, cooled, poured into 1000 ml water, and extracted with ether. The extract was washed with brine, dried (MgSO4), and concentrated. Kugelrohr distillation of the residual oil gave 23.3 g of the desired product as a light yellow oil b.p. 90°-95° C. (1 mm Hg).
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C(Cl)=O)CCC=1>C(Cl)Cl>[C:1]1([C:5]([O:7][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])[CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)C1=CCC1
Reactant: Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C1=CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)C1=CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 47.3 %

Procedure:
Cyclobut-1-enecarboxylic acid (0.51 mmol, 50 mg) was dissolved in 0.5 ml dry CH2Cl2. The solution was cooled to 0° C. and oxalyl dichloride (0.51 mmol, 43 μl) was added. The temperature of the solution was raised to room temperature, and the mixture was allowed to react for 1 h. The solvent was evaporated to generate a viscous oil. Phenol (0.51 mmol, 48 mg) and triethylamine (1.02 mmol, 142 μl) were dissolved in 0.5 ml dry CH2Cl2, and the solution was stirred at 0° C. for 45 min before being added to a vial containing the cyclobut-1-enecarboxylic chloride. The reaction mixture was stirred for 16 h at rt. The reaction was quenched with 1 N HCl, and was extracted with CH2Cl2 (30 ml). The CH2Cl2 solution was washed with 5% NaHCO3 (2×10 ml), dried over Na2SO4, concentrated by rotary evaporation, and then purified by flash column chromatography (100% CH2Cl2) to yield 11 as a colorless oil (42 mg, 47%). 1H-NMR (100 MHz) δ 7.42 (m, 2H), 7.28 (m, 1H), 7.14 (m, 2H), 7.02 (s, 1H), 2.88 (t, J=3.0 Hz, 2H), 2.60 (m, 2H). 13C-NMR (400 MHz) δ 160.5, 150.8, 149.2, 138.3, 129.6, 125.9, 121.8, 29.5, 27.7. HRMS (EI) calcd. for C11H10O2 [M]+ 174.0679, found 174.0681.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CC=CC=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)(=[O:16])=[O:15]
Reactant: OC1CC=CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CC=CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
3-Cyclopentene-1-ol (0.500 g, 5.94 mmol) was stirred in DCM (95 mL). Pyridine (2.40 mL), N,N-dimethylaminopyridine (0.10 g, 1.00 mmol) and methanesulfonyl chloride (0.690 mL, 8.92 mmol) were added, and the reaction mixture was stirred at 35° C. for 4 h. N,N-Dimethylaminopyridine (0.14 g, 1.2 mmol) and methanesulfonyl chloride (0.69 mL, 8.92 mmol) were added, and the reaction was stirred overnight. TLC indicated complete conversion. The reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography, eluting with DCM, to afford the title compound as a clear oil (0.660 g, 68%).
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[N:16]=[CH:15][CH:14]=[N:13][C:12]=1[S:11]2.Cl>CN(C=O)C>[OH:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[N:16]=[CH:15][CH:14]=[N:13][C:12]=1[S:11]2
Reactant: COc1ccc2c(c1)Sc1nccnc1N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)Sc1nccnc1N2
Yield: 23 %

Procedure:
Sodium hydride (60 mg, 2.5 mmoles) was added to ethanethiol (124 mg, 2 mmoles) in dry DMF (2 ml) under argon. 7-Methoxy-1,4-diaza-10H-phenothiazine (462 mg, 2 mmoles) was then added and the reaction mixture was refluxed for 3 hours. The mixture was poured into 0.5N HCl (50 ml). The solid was collected, washed with methanol and air-dried to yield starting material. Extraction of the filtrate with ethyl acetate gave 100 mg of a mixture that was chromatographed on silica gel, eluting with 40% ethyl acetate in hexane to yield 25 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([N:11]1[C:12](=[O:20])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:23]1=[O:24])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccccc1N)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](c1ccccc1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (S)-(2-amino-benzoylamino)-phenyl-acetic acid methyl ester (330 mg, 1.16 mmol) in THF (30 mL) is added trichloromethyl chloroformate (115 mg, 0.58 mmol). The mixture is stirred at 90° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated to give the (S)-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl-acetic acid methyl ester (110 mg, 31%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[S-:20][C:21]#[N:22].[K+]>CN(C=O)C.O>[Cl:19][C:15]1[CH:14]=[C:13]([C:3]2[NH:2][C:21](=[S:20])[NH:22][C:4]=2[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: N#C[S-]
Reactant: NC(C(=O)c1ccc(F)cc1)c1ccnc(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1

Procedure:
With gentle heating, 23a (2.9 g; about 9.6 mmol) was dissolved in absolute DMF (75 ml). Potassium thiocyanate (1.9 g; 19.6 mmol) was introduced into the clear orange-red solution: immediate opalescence and a lighter color. The reaction mixture was stirred under reflux for 1.5 h. The suspension was cooled to room temperature and, with H2O cooling, diluted dropwise with H2O (about 140 ml). The yellow precipitate was filtered off, washed with H2O and dried under reduced pressure over CaCl2.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=O)=[CH:10][CH:9]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[CH:1][CH3:2])=[CH:10][CH:9]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=C1CCc2ccc(Br)cc21
Reaction time: 1 h
Yield: 74 %

Procedure:
(Ethyl)triphenylphosphonium bromide (14.5 g, 39.1 mmol) was dissolved in 75 mL of tetrahydrofuran followed by addition of potassium tert-butoxide (5.29 g, 47.3 mmol) at room temperature. Upon completion of the addition, the reaction mixture was stirred for 1 hour. A solution of 6-bromo-indan-1-one 38b (3.39 g, 18.6 mmol) in 25 mL of tetrahydrofuran was added to above mixture and the mixture was stirred for another 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction was quenched with 150 mL of water and then the mixture was extracted with dichloromethane (50 mL×4). The combined organic extracts were washed with saturated brine (45 mL×2), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-ethylidene-indan 41a (3.07 g, 74%) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:16]([NH:18][C@H:19]([C:24]([O:26][CH2:27][C@H:28]1[O:32][C@@H:31]([N:33]2[CH:40]=[C:39]([F:41])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[C@H:30]([OH:42])[C@@H:29]1[OH:43])=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:4].[CH2:44]([O:51][C:52]([NH:54][C@H:55]([C:71](O)=[O:72])[CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[CH2:44]([O:51][C:52]([NH:54][C@H:55]([C:71]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:16]([NH:18][C@H:19]([C:24]([O:26][CH2:27][C@H:28]1[O:32][C@@H:31]([N:33]2[CH:40]=[C:39]([F:41])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[C@H:30]([OH:42])[C@@H:29]1[OH:43])=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:4])=[O:72])[CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:62])=[O:53])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
1.04 Grams (1.65 mmol) of 5'-O-{N-(N-alanylphenylalanyl)isoleucyl}-5-fluorouridine hydrochloride obtained in Example 9 was dissolved in dimethylformamide (10 ml), and 0.815 g (1.97 mmol) of Nα,Nε -di-benzyloxycarbonyllysine and 0.375 g (2.30 mmol) of diethylphosphoryl cyanide were then added. To this solution was added under ice-cooling 0.60 g (5.90 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. The reaction liquid was concentrated under reduced pressure, and the residue was subjected to separation/purification by way of silica gel column chromatography (first time: a linear gradient of chloroform containing 2%→6% methanol; second time: a linear gradient of chloroform containing 3%→6% methanol) whereby 0.85 g (52.3%) of 5'-O-[N-[N-{N-(Nα,Nε -dibenzyloxycarbonyllysyl)alanyl}phenylalanyl]isoleucyl]-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:23])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.O>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@@H]12

Procedure:
3-Acetoxy-oestra-1,3,5(10)-trien-17β-ol (500 mg., 1.6 mmole) in pyridine (2 ml.) was treated at room temperature for 16 hr. with methanesulphonyl chloride (1 ml.). The solution was diluted slowly with water (25 ml.) then the product was extracted into ether (50 ml.). The extract was washed with 2N-sulphuric acid (25 ml.) then water (50 ml.) and the solvent was evaporated in vacuo. Crystallisation of the residue from slightly aqueous methanol gave the title compound in two crops (total 519 mg., 93%), m.p. 120°-122°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2
Reactant: Cn1ccc2cc(O)ccc21
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4c(ccn4C)c3)ncnc2cc1OCCCN1CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (400 mg, 1.24 mmol), (prepared as described for the starting material in Example 9), potassium carbonate (500 mg, 3.62 mmol), 5-hydroxy-1-methylindole (231 mg, 1.57 mmol), (prepared as described for the starting material in Example 291), and DMA (5.0 ml) for 5 minutes. The mixture was then stirred at 90° C. for 3 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography, gradient elution, with dichloromethane/methanolic ammonia (7M), (100/0 to 90/10) to give 6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)prop oxy)quinazoline (247 mg, 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[C:24]([C:27]#[N:28])[O:25][CH:26]=1>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[C:24]([C:27]#[N:28])[O:25][CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: N#Cc1cc(Br)co1
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromo-2-cyanofuran generally according to the procedures described in examples 82 and 1. A white solid: mp 99-100° C.; 1H NMR (DMSO-d6): δ 10.04 (s,1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.54-7.61 (m, 3H), 7.22 (d, J=8.45 Hz, 1H), 6.99 (dd, J=4.99, 3.60 Hz, 1H), 6.90 (dd, J=3.48, 1.02 Hz, 1H), 4.40, (d, J=15.42, 1H), 3.94 (d, J=15.47 Hz, 1H), 2.5 (m, 2H), 0.76 (t, J=7.02 Hz, 3H); MS (ESI) m/z 365 ([M+H]+); MS (ESI) m/z 363 ([M−H]−); Anal. calcd for C20H16N2O3S: C: 65.92; H: 4.43; N: 7.69. Found: C: 64.84; H: 4.59; N: 6.98.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C[Si](OP(=O)=O)(C)C>>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[NH:20][C:18](=[O:19])[C:17]2[C:16](=[CH:24][C:23]([O:25][CH3:26])=[CH:22][CH:21]=2)[N:15]=1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: COc1ccc(C(N)=O)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Product: COc1ccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 115 °C
Yield: 16.8 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (2.3 g, 10.8 mmol) and 2-amino-4-methoxybenzamide (1.5 g, 9.0 mmol) were combined with trimethylsilyl polyphosphate (15 mL) and the mixture was heated at 115° C. for 18 h with vigorous stirring. To mixture was allowed to cool to rt, and then was partitioned between were water (15 mL) and EtOAc (15 mL). The organic layer was separated and the aqueous layer (pH˜1) was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:10 to 1:1 EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4(3H)-one (487 mg) as an off-white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=O.[CH3:12][NH2:13].[BH4-].[Na+]>CO>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][NH:13][CH3:12])[CH:8]=[CH:9]1
Reactant: CN
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of 7-formyl-1H-indole (0.23 g, 1.6 mmol) in methanol (10 mL) was added with a 40% solution of methylamine in methanol (0.6 mL, 6.4 mmol), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was added portionwise with sodium borohydride (0.060 g, 4.8 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, then the residue was added with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (99:1→95:5)) to obtain 1-(1H-indole-7-yl)-N-methylmethanamine (0.23 g, 89%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13].C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:20]1[CH2:21][CH2:22][N:17]([S:14]([C@@H:12]([C@:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])([OH:29])[CH2:23][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]1)(=[O:39])[CH3:38]
Reactant: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(S(=O)(=O)[C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Reaction time: 0.5 h

Procedure:
In dichloromethane (10 ml) was dispersed 1[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H ,1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine.dihydrochloride (Compound 20, 0.40 g) obtained in Working Example 14. To the dispersion were added, under ice-cooling, triethylamine (0.40 ml) and acetic anhydride (0.13 g). The mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was then washed with water, dried and concentrated. The concentrated was subjected to a silica gel chromatography (eluent: dichloromethane/methanol=20/1) for purification. The object fraction was concentrated and processed with hydrogen chloride, followed by addition of isopropyl ether to give 1-acetyl-4-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine (Compound 25).hydrochloride (336 mg) as colorless powder.
Reaction SMILES: [OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([O:28]C2CCCCO2)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=3.O[CH2:36][CH2:37][C:38]([O:40]CC1C=CC=CC=1)=[O:39].CN(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CC(OC)(C)C>[OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([O:18][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:17])[CH:10]=[CH:9][CH:8]=3
Reactant: O=C(CCO)OCc1ccccc1
Reactant: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)O)CC21)OC1CCCCO1
Agent: CN(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCCCCC(O)CCC1C(O)CC2Cc3c(cccc3OCC(=O)OCCC(=O)O)CC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Compound B (120 mg, 0.25 mmol), benzyl 3-hydroxypropionate (54 mg, 0.30 mmol) and trimethylamine (140 μL, 1.0 mmol) in DCM (4 mL) was added BOP—Cl (95 mg, 0.38 mmol). The reaction mixture was stirred at RT for 16 hr under nitrogen, diluted with MTBE, washed with brine, dried over sodium sulfate, and concentrated to an oil that was purified by silica gel chromatography. A solution of the THP-protected diester in ethanol (4 mL) was treated with PPTS (50 mg), stirred at 50° C. for 4 hr, and concentrated to an oil that was purified by silica gel chromatography. A solution of the THP-deprotected diester in dioxane (5 mL) was treated with wet 5% Pd/C (20 mg) and stirred for 24 hr under a balloon of hydrogen. The reaction mixture was filtered and concentrated to give crude Compound II-4. MS: m/z 485 [M+Na]+
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH3:12])[CH2:2][CH3:3].Br[N:14]1C(=O)CC[C:15]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CNN>CCOCC.C(Cl)(Cl)(Cl)Cl>[CH2:2]([C:1]1[N:14]([CH3:15])[C:10]([CH2:11][CH3:12])=[C:5]2[C:4]=1[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:3]
Reactant: CCCc1ccccc1CCC
Reactant: O=C1CCC(=O)N1Br
Agent: CNN
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1c2ccccc2c(CC)n1C

Procedure:
A mixture of 0.374 mole of o-dipropylbenzene, 146 g. (0.822 mole) of N-bromosuccinimide, 0.1 g. of benzoyl peroxide, and 800 ml. of carbon tetrachloride is heated under reflux with stirring and ultraviolet irradiation until the reaction is complete. The precipitated succinimide is filtered, washed with carbon tetrachloride, and the filtrate is evaporated to dryness under reduced pressure. The residual α,α'-dibromo-o-dipropylbenzene is dissolved in 800 ml. of absolute ether. To the stirred solution under nitrogen is added dropwise a solution of 40 g. (0.87 mole) of methyl hydrazine in 50 ml. of absolute ether. A gummy precipitate separates. After 3 hours of stirring and an overnight period of standing, the ether is decanted. The residue dissolved in 625 ml. of water is treated with 375 ml. of 40% sodium hydroxide solution and the mixture is stirred at reflux for 1.5 hours. After cooling, the precipitate of the crude product is collected, washed with water, and dissolved in 600 ml. of ether. The ether solution is washed repeatedly with water and dried over anhydrous magnesium sulfate with stirring and cooling in an ice bath. The filtered solution is evaporated under reduced pressure and the residual dark yellow solid is triturated with petroleum ether, filtered and dried in vacuo to yield 1,3-diethyl-2-methylisoindole.
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1.C[O-:16].[Na+]>CO>[OH:16][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: C[O-]
Reactant: O=c1[nH]cc(-c2ccncn2)cc1Br
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]cc(-c2ccncn2)cc1O

Procedure:
A mixture of 5.0 g of 3-bromo-5-(4-pyrimidinyl)-2-(1H)-pyridone, 6.0 g of sodium methoxide and 100 ml of methanol is autoclaved at 200° for twelve hours. The solvent is distilled off in vacuo and the residue treated with water. The aqueous mixture is neutralized with acetic acid and the resulting solid collected, washed with water and dried. Recrystallization from dimethylformamide with a hot filtration yields the desired product.
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[Cl-:11].[CH3:12][N:13]([CH3:39])[C:14]1[CH:38]=[CH:37][C:17]([CH:18]=[N:19][N+:20]2[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:21]=2[CH3:36])=[CH:16][CH:15]=1.CCOCC>CN(C)C=O>[Cl-:11].[CH3:35][N:33]([CH3:34])[C:30]1[CH:31]=[CH:32][C:27]([CH:26]=[N:25][N+:22]2[CH:23]=[CH:24][N:20]([N:19]=[CH:18][C:17]3[CH:16]=[CH:15][C:14]([N:13]([CH3:12])[CH3:39])=[CH:38][CH:37]=3)[C:21]=2[CH:36]=[CH:4][N:5]([CH3:7])[CH3:6])=[CH:28][CH:29]=1
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: CCOC(OCC)N(C)C
Agent: [Cl-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C=Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 96 h

Procedure:
73.5 g of N,N-dimethylformamide diethyl acetal are added to 20.5 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride in 400 ml of dry dimethylformamide. After stirring at 50° for 4 days, the mixture is left to cool. Then, 250 ml of ether are added thereto and the product is removed by filtration and is recrystallized from dry ethanol. There is obtained 1,3-bis[[p-(dimethylamino) benzylidene]amino]-2-[2-(dimethylamino)vinyl]imidazolium chloride of melting point 265° (decomposition).