Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1.Cl.[OH-].[Na+]>O1CCOCC1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH:3]=[CH:2][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]3)[CH2:6][CH2:7]1
Reactant: COc1ccccc1N1CCN(CCC(O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CC=Cc2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.8 Grams of 6- {-1-hydroxy-3-[4-(2-methoxy- phenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril was dissolved in 100 ml of dioxane and 5 ml of concentrated hydrochloric acid was added thereto, then the mixture was refluxed for 15 minutes. The reaction mixture was concentrated under a reduced pressure to dryness to obtain a residue. To the residue were added 10N-NaOH and further and stirred at a room temperature for 30 minutes to precipitate crystals. The crystals were collected by filtration, washed with ether then recrystallized from ethanol- chloroform-acetone to obtain 6-{3-[4-(2-methoxyphenyl)- 1-piperazinyl]-1-propenyl}-3,4-dihydrocarbostyril in colorless needle-like crylstals. Yield: 2.3 g. Melting point: 174°-175° C.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=[O:6].FC(F)(F)C(O[BH3-])=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=NOC)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH3:34])[CH:20]=1.Cl.[OH-].[Na+]>C1COCC1.O.C(Cl)Cl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:6])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH3:34])[CH:20]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C(=NOC)c1ccc(Br)cc1C
Agent: Cl
Agent: [BH3-]OC(=O)C(F)(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a suspension of NaBH4 (5.56 g, 147 mmol) in THF (100 mL) was added dropwise trifluoroacetic acid (16.7 g, 147 mmol) at a rate which maintained the reaction temperature between 25 and 35° C., and the resulting slurry was stirred at room temperature for 30 minutes. To the trifluoroacetoxyborohydride suspension was added a solution of ethyl (4-bromo-2-methylphenyl)-(methoxyimino)ethanoate (11.0 g, 36.7 mmol) in 20 mL of THF. The resulting light yellow mixture was stirred at reflux for 3.5 h and then at room temperature for 16 h. The excess NaBH4 was neutralized by the careful addition of conc. HCl (pH<3). The pH was adjusted to >9 with 50% aq. NaOH and the alkaline mixture was diluted with water (100 mL). The THF was evaporated and the aq. residue was extracted with CH2Cl2 (3×100 mL). The organic extracts were washed with brine, dried (Na2SO4), filtered, and the CH2Cl2 was removed in vacuo to give crude product as a yellow oil. The oil was dissolved in CH2Cl2 and anhydrous HCl was bubbled into the solution. The resulting HCl salt was collected by vacuum filtration and dried to give the desired product as a white solid (5.7 g, 58%). mp 211-214° C. (d); 1H NMR (DMSO-d6) δ 2.35 (s, 3H), 3.67 (d, 2H, J=6.0 Hz), 4.39 (m, 1H), ˜5.30 (bs, 1H), 7.45-7.48 (m, 2H), 7.56 (d, 1H, J=8.8 Hz), 8.66 (s, 3H).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[OH:13][C:14](O)([CH3:20])[C:15](=O)[CH2:16]CC.C1COCC1>C(N(CC)CC)C>[C:14]([C:15]1([CH3:16])[CH2:7][O:6][C:5](=[O:11])[O:4][CH2:2]1)(=[O:13])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCC(=O)C(C)(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a one liter three neck flask equipped with a mechanical stirrer and under nitrogen were added triphosgene (37.0 g), 3,3 dihydroxyethyl-2-butanone (50 g) and THF (300 mL). The resulting mixture was stirred until a homogeneous solution resulted. This homogeneous solution was cooled to −78° C. Triethylamine (75.0 g) was added to the this solution over 30 min. The cold bath was removed and the reaction allowed to warm to room temperature. After stirring for one hour at room temperature the triethylamine/HCl salt was removed by filtration and the filtrate pass through a silica gel plug. The solvent was removed under reduced pressure resulting in an off white product. This product was then washed with hot ether giving a white solid. NMR analysis indicated that the product contained a small amount of triethylamine/HCl salt, thus the material was dissolved in dichloromethane and washed with water affording 15.02 g of material. 1H NMR (CDCl3) ppm: 4.70 (ab doublet, 2H), 4.20 (ab doublet, 2H), 2.3 (S, 3H), 1.25 (S, 3H).
Reaction SMILES: [SH:1][C:2]1[C:3](=[O:11])[N:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:1][C:2]2[C:3](=[O:11])[N:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: CCCn1ccnc(S)c1=O
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1ccnc(SCc2ccc(Cl)cc2)c1=O
Yield: 88 %

Procedure:
500 mg (2.30 mM) of 3-mercapto-1-propylpyrazin-2(1H)-one, 319.2 μl (1.21 mM) of 4-chlorobenzylbromide and 637 mg (4.6 mM) of potassium carbonate in 4 ml of tetrahydrofurane were stirred overnight at room temperature. Water was added and the aqueous layer was extracted with ethyle acetate. The organic layer was separated and washed with water, dried on anhydrous sodium sulfate and evaporated under vacuum, to give an oil which was purified by silica gel column chromatography, using dichloromethane/dimethylketone (98/2) as eluant, to give 600 mg of 3-[(4-chlorobenzyl)thio]-1-propylpyrazin-2(1H)-one. Yield: 88%.
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:14]([O:6][CH2:7][C@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C1CC[C@@H](CO)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
Imidazole (4.09 g, 60 mmols) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) were added to a CH2Cl2 (85 ml) solution of (5S)-5-(hydroxymethyl)-2-pyrrolidinone (3.14 g, 27.3 mmols). Then, with the mixture being cooled with ice, a CH2Cl2 (15 ml) solution of tert-butyldimethylsilyl chloride (4.53 g, 30 mmols) was added, and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 300 g, MeOH—CHCl3 5:95 v/v) to obtain (5S)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (6.22 g, 99.5%): [α]D27+42.32 (c 1.136, CHCl3). IR νmax (film) cm−1: 3242, 1697. 1H-NMR (CDCl3)δ: 5.79 (1H, br), 3.80-3.71 (1H, m), 3.63 (1H, dd, J=9.9, 3.8 Hz), 3.44 (1H, dd, J=9.9, 7.7 Hz), 2.44-2.26 (2H, m), 2.24-2.11 (1H, m), 1.80-1.67 (1H, m), 0.89 (9H, s), 0.06 (6H, s). MS m/z: 230 (M++1), 214 (M+−15), 172 (100%). HRMS: Calculated for C10H20NO2Si: 214.1263 (M+−15). Found: 214.1240 (M+−15).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].C(=O)(O)[O-].[Na+]>COCCOCCOC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[S:17]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Product: COc1cc2[nH]ccc(=S)c2cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
After suspending the 6,7-dimethoxy-1H-quinolin-4-one (10.3 g, 50.0 mmol) described in WO9717329, phosphorus pentasulfide (26.7 g, 60.0 mmol) and sodium bicarbonate (26.7 g, 318 mmol) in diglyme (diethyleneglycol dimethyl ether) (100 ml), the suspension was heated and stirred at 80° C. for 2 hours. The reaction solution was returned to room temperature and poured into ice water (1000 ml), and the precipitated crystals were filtered out, washed with water and blow-dried to obtain the title compound (8.19 g, 37.0 mmol, 74%) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([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.Cl.[OH:22][C:23]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([N:33]([CH3:35])[CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(Cl)cc3)nc3ccccc13)C2
Yield: 8 %

Procedure:
Reaction of 2-(4-chlorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 30 (8% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.74-3.10 (m, 8H), 3.58 and 4.21 (2t, 2H), 4.48 and 5.10 (2s, 2H), 6.34 and 6.88 (2d, 1H), 6.96 and 7.17 (2d, 1H), 7.48-8.16 (m, 7H), 8.57-8.62 (m, 2H); MS (ESI) m/z 459 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[CH:16][C:15]=2[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>CC(C)=O>[CH3:39][O:38][C:36](=[O:37])[CH2:35][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[C:15]=3[CH:16]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(9-benzyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenol (0.419 g, 1.185 mmol) was reacted with K2CO3 (0.213 g, 1.541 mmol) and methyl bromoacetate (0.236 g, 1.541 mmol) in acetone to give the product (0.362 g, 0.851 mmol, 72%) as a white solid, mp 109-112° C. 1H NMR (DMSO-d6) δ 1.77-1.87 (m, 4H), 2.65 (t, J=5.3 Hz, 2H), 2.70 (t, J=6.0 Hz, 2H), 3.71 (s, 3H), 4.81 (s, 2H), 5.33 (s, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.03 (d, J=7.3 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.25-7.30 (m, 3H), 7.39 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.58 (d, J=1.1 Hz, 1H); [ESI(+)], m/z 426 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+].C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1)[CH3:43]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), rhodium(I) acetate (0.023 g) and methylene chloride (10 mL) was added dropwise ethyl diazoacetate (0.64 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 59%).
Reaction SMILES: C1(C[O:8][C:9](=[O:52])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48]([O:50][CH3:51])=[O:49])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48]([O:50][CH3:51])=[O:49])[CH:24]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:52])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 93.6 %

Procedure:
A mixture of 2.63 g (3.67 mmol) of N-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 150ml of THF was shaken in a hydrogen atmosphere at room temperature for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from methanol-water to give 1.84 g (93% yield, mp 119°-123°) of N-(carboxymethyl)-N-[3-(methoxy-carbonyl)-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[OH-].[Na+]>CCO.C1COCC1>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A solution of ethyl 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinate (300 mg, 0.770 mmol) in EtOH (6 mL) and THF (6.00 mL) was treated with 30% aqueous sodium hydroxide (2 mL, 26.0 mmol) and stirred at rt for 3 hrs. Remove most of the solvent on rotary evaporator and acidified with 1N HCl (no precipitate formed) and extracted into CH2Cl2 several times and the combined extracts were concentrated to give 240 mg of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid. LCMS: (M+H)+=362.02, 363.93 (Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[S:22](Cl)(=[O:24])=[O:23]>O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[S:22]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1nc2ccc(O)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2ccc(OS(=O)(=O)c3c(F)cccc3F)cc2s1
Temperature: 20 °C
Reaction time: 120 h
Yield: 102 %

Procedure:
To a solution of 1 g of 2-amino-1,3-benzothiazol-6-ol in 66 cm3 of aqueous 0.1N sodium hydroxide solution are added 1.279 g of 2,6-difluorobenzenesulfonyl chloride. The solution is stirred for 5 days at a temperature in the region of 20° C. After addition of 10 cm3 of water, the precipitate is filtered off by suction and then washed with twice 3 cm3 of ice-cold water and dried under reduced pressure over phosphorus pentoxide. 2.1 g of 2-amino-1,3-benzothiazol-6-yl 2,6-difluorobenzenesulfonate are obtained in the form of a pink powder, the characteristics of which are as follows:
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]([NH2:24])=[S:23])=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=O)[CH2:42]Br)[CH2:37][CH2:36]1)(=[O:34])[CH3:33].[ClH:45]>C(O)C>[ClH:45].[ClH:45].[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:23][CH:42]=[C:41]([CH:38]3[CH2:39][CH2:40][N:35]([C:32](=[O:34])[CH3:33])[CH2:36][CH2:37]3)[N:24]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)Nc1ncc(Sc2ccccn2)cc1Oc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)CBr)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Yield: 76.2 %

Procedure:
A mixture of 1-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)thiourea (0.075 g, 0.21 mmol), triethylamine (0.073 mL, 0.53 mmol), and 1-(1-acetylpiperidin-4-yl)-2-bromoethanone (0.087 g, 0.26 mmol) was refluxed in Ethanol (10 mL) for 3 hours. The reaction was concentrated and the residue was purified by silica gel (1% MeOH in CH2Cl2) to provide 1-(4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone dihydrochloride (0.093 g, 76.2% yield) after HCl salt formation. 1H NMR (d6-DMSO) δ 8.38 (m, 1H), 8.29 (d, 1H), 7.67 (dt, 1H), 7.45-7.37 (m, 3H), 7.21-7.08 (m, 5H), 6.78 (s, 1H), 4.32 (d, 1H), 3.87 (d, 1H), 3.13 (t, 1H), 2.87 (m, 1H), 2.64 (t, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.63-1.39 (m, 2H).
Reaction SMILES: Cl.NC1C=C(C(F)(F)F)C=CC=1S.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[CH:18][C:19]2[S:23][CH2:22][NH:21][C:20]=2[CH:24]=1.C=O.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:41])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>ClCCl.O.C(N(CC)CC)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:41])[C:38]=1[O:39][CH3:40])[C:33]([N:21]1[C:20]2[CH:24]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=[CH:18][C:19]=2[S:23][CH2:22]1)=[O:34]
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1Cl
Reactant: FC(F)(F)c1ccc2c(c1)NCS2
Agent: C=O
Agent: Cl
Agent: Nc1cc(C(F)(F)F)ccc1S
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(C(=O)N2CSc3ccc(C(F)(F)F)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-amino-4-trifluoromethylbenzenethiol hydrochloride (502 mg), and 5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole synthesized from 37% formalin (0.18 mL) and triethylamine (0.30 mL) in the same manner as in Example 38 were dissolved in dichloromethane (5 mL), and triethylamine (0.30 mL) and 3,5-dichloro-4-methoxybenzoyl chloride (354 mg) were added to the solution, and then the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the title compound (223 mg) as a colorless oily substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][N:15]=2)[C:11]=1[SH:12])=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][N:15]=2)[C:11]=1[SH:12])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2ncnn2c1S
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cnc2ncnn2c1S
Temperature: 80 °C
Yield: 95.2 %

Procedure:
The product obtained in Step 2 (2.4 g) was dissolved in 50 ml of aqueous solution containing 1.0 g potassium hydroxide, the solution was heated at 80° C. for one hour, the insoluble matters were filtered off, and the clear, faint yellow filtrate was washed with 30 ml ethyl acetate. The pH of the aqueous layer was lowered to 1.0 with concentrated hydrochloric acid, and the crystals thus formed were collected by filtration, affording 2.0 g of the objective compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:16]=[CH:15]3)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3[nH]ccc3c2)C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(S(=O)(=O)n2ccc3cc(C4CN(C(=O)OC(C)(C)C)C4)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
3-(1H-Indol-5-yl)-azetidine-1-carboxylic acid tert-butyl ester (135 mg, 0.5 mmol) was dissolved in DMF (10 ml) and cooled to 0° C. Sodium hydride (35.7 mg, 0.74 mmol) was added, and the reaction mixture was stirred for 1 hour at 0° C. 4-Isopropyl-benzenesulfonyl chloride (98 μl, 0.55 mmol) was added slowly to the reaction mixture. Stirring was continued for 10 minutes. Cold water (100 ml) was added to the reaction mixture, and it was extracted twice with diethyl ether (80 ml). The organic layer was dried over magnesium sulphate, filtered, and the solvent was evaporated under reduced pressure to give a crystalline solid (75 mg, 33%). ESI-MS [m/z]: 355.15 [M-(Boc)+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(OO[CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1)(=O)=O>CN(C=O)C>[O:46]=[S:42]1(=[O:45])[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][CH2:36][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][CH:17]=[C:16]5[CH3:22])=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:23][CH3:24])[CH2:40][CH2:41]1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OOCCCN2CCS(=O)(=O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (600 mg, 1.87 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (773 mg, 5.60 mmol) and 3-(1,1-dioxothiomorphlino)propoxy tosylate (1.296 g, 3.74 mmol) in DMF (30 ml) was stirred at 75° C. overnight and allowed to cool to ambient temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) and the product recrystallised from ethanol to give 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (525 mg, 56%).
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[C:6]([CH3:14])[CH2:5][CH2:4]1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][CH:3]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[C:6]([CH3:14])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1C=C(C)CCC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1C=C(C)CCC1CO
Reaction time: 2 h

Procedure:
To ethyl(1R/S,6R/S)-6-formyl-3-methylcyclohex-2-ene-1-carboxylate (516 mg, 2.6 mmol) in methanol (13 mL) at 0° C. was added NaBH4 (199 mg, 5.3 mmol) and the reaction mixture was stirred for 2 h. Water was added, the product extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the product was purified by flash chromatography over silica gel (ethyl acetate/hexanes, 20/80 to 40/60) to afford ethyl(1R/S,6R/S)-6-(hydroxymethyl)-3-methylcyclohex-2-ene-1-carboxylate.