Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([S:19][CH2:20][CH:21]([CH2:25][C:26](=O)[NH2:27])[C:22]([OH:24])=[O:23])(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([S:19][CH2:20][CH:21]([CH2:25][C:26]#[N:27])[C:22]([OH:24])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(=O)SCC(CC#N)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dicyclohexylcarbodiimide (1.03 g.) is added to a solution of 3-acetylthio-2-carbamoylmethylpropanoic acid (1.02 g.) in pyridine (18 ml.). After five hours stirring at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness, the residue is dissolved in ethyl acetate and extracted with saturated aqueous bicarbonate. The aqueous phase is acidified and extracted with ethyl acetate. This organic layer is dried and concentrated to dryness. The residue, 3-acetylthio-2-cyanomethylpropanoic acid is crystallized from ether-hexane, m.p. 110°-112°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[CH:21][C:11]3[N:12]=[C:13]([CH2:15][C:16]([O:18]CC)=O)[S:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH3:26][C:27]1[O:31][C:30]([CH2:32][NH2:33])=[N:29][N:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:22]=[CH:21][C:11]3[N:12]=[C:13]([CH2:15][C:16]([NH:33][CH2:32][C:30]4[O:31][C:27]([CH3:26])=[N:28][N:29]=4)=[O:18])[S:14][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc2ccc(-c3ccc(F)cc3)cc2s1
Reactant: Cc1nnc(CN)o1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc(CNC(=O)Cc2nc3ccc(-c4ccc(F)cc4)cc3s2)o1
Reaction time: 2 h
Yield: 80 %

Procedure:
Ethyl 2-(6-(4-fluorophenyl)benzo[d]thiazol-2-yl)acetate (described in WO2011/074560, 500 mg, 1.59 mmol) in THF (4 mL) was treated with sodium hydroxide (1N NaOH, 1.9 mL, 1.9 mmol). After 2 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was co-evaporated with toluene (5 mL), re-dissolved in DMF (4 mL), and treated with (5-methyl-1,3,4-oxadiazol-2-yl)methanamine hydrochloride (284 mg, 1.90 mmol), TEA (2.2 mL, 16 mmol) and PyBOP (990 mg, 1.9 mmol). After 16 hours, the reaction mixture was diluted with water (20 mL), extracted with DCM (3×10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (eluting with 0-20% DCM/MeOH) to give Compound A9a (485 mg, 80.0% yield) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])(=[O:7])=[O:6].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1.C1N2CCN(CC2)C1>ClCCl>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([NH:20][C:18]([NH:17][S:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:5]([CH2:4][CH2:3][O:2][CH3:1])(=[O:7])=[O:6])(=[O:15])=[O:16])=[O:19])[N:22]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: COCCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COCCS(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 2-[(2-methoxyethyl)sulfonyl]benzenesulfonyl isocyanate (1.7 g, 0.0057 mol) in dichloromethane (10 ml) was added to 2-amino-4,6-dimethoxypyrimidine (0.70 g, 0.0045 mol) and DABCO (catalytic amount); the mixture was stirred at room temperature under nitrogen overnight. Filtration gave N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-[(2-methoxyethyl)sulfonyl]benzenesulfonamide (1.43 g) as a white powder, m.p. 187°-192°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2Br)=[O:11])[C:5]([OH:8])=[CH:6][CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:13]3[S:14][C:15]([CH3:18])=[CH:16][C:12]=3[C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc(Cl)ccc1O)c1ccsc1Br
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Oc1ccc(Cl)cc1NC2=O
Temperature: 145 °C
Reaction time: 1.25 h
Yield: 20.1 %

Procedure:
To a solution of N-(3-chloro-6-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide (4.1 g) in dimethyl sulfoxide (33 ml) was added potassium carbonate (3.3 g), and the mixture was stirred at 140-150° C. for 75 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration. The filtrate was extracted twice with chloroform, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue and the above-mentioned crystals were combined and purified by silica gel column chromatography (chloroform:methanol=20:1, hexane:ethyl acetate=1:1-ethyl acetate:methanol=20:1). The obtained solid was collected by filtration from hexane-ethyl acetate to give 7-chloro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (660 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:9]2[N:16]=[CH:17][N:18]=[C:8]2[NH:7][C:6]=1[CH3:19])=[O:4].[Br:20]Br.O>C(O)(=O)C>[Br:20][CH2:19][C:6]1[NH:7][C:8]2[N:9]([N:16]=[CH:17][N:18]=2)[CH:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: BrBr
Reactant: COC(=O)C1=C(C)Nc2ncnn2C1c1cccs1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1=C(CBr)Nc2ncnn2C1c1cccs1
Yield: 50.6 %

Procedure:
In 300 ml of acetic acid is dissolved 29.5 g of 6-methoxycarbonyl-5-methyl-7-(2-thienyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine at 60° C. To the solution is added dropwise a solution of 16 g of bromine in 50 ml of acetic acid for 20 minutes with stirring. After stirring at room temperature for an hour, the reaction mixture is poured into water, extracted with chloroform, washed with water and potassium carbonate solution, dried and the solvent is evaporated under reduced pressure. The obtained pale yellow crystals are recrystallized from ethanol to give 18 g of 5-bromomethyl-6-methoxycarbonyl-7-(2-thienyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 155° C. with decomposition.
Reaction SMILES: [N:1](C(OCC1C=CC=CC=1)=O)([CH2:3][C:4]([NH:6][C@H:7]([C:16]([NH:18][C@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].O.O.C(O)(=O)C(O)=O>CO.[Pd]>[NH:1]([CH2:3][C:4]([NH:6][C@H:7]([C:16]([NH:18][C@H:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: CNCC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C

Procedure:
The oily Z-Sar-Asp(OtBu)-Val-OtBu protected tripeptide obtained in a yield of 4.2 g (7.6 mmol) (Rf1 =0.75) is dissolved in 40 ml of methanol and, after adding 0.8 g of palladium-on-carbon catalyst, the mixture is hydrogenated in the usual manner. After filtering off the catalyst, 1.0 g (8.0 mmol) of oxalic acid dihydrate is added to the filtrate, the solution is evaporated and the residue is solidified by adding ether to obtain 2.24 g of H-Sar-Asp(OtBu)-Val-OtBu.oxalate (free tripeptide oxalate), m.p.: 190°-192° C., Rf3 =0.30.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[CH:2].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH4+].[OH-]>O1CCOCC1.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)#[CH:2]
Reactant: CN1CCNCC1
Reactant: C#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C#Cc1cccc(CN2CCN(C)CC2)c1
Yield: 37.9 %

Procedure:
3-Ethynylbenzaldehyde (90 mg, 0.69 mmol) and 1-methylpiperazine (92 μL, 0.828 mmol) in 1,4-dioxane (2.6 mL), under a nitrogen atmosphere, at room temperature were treated first with TFA (128 μL, 1.66 mmol), then with sodium triacetoxyborohydride (210 mg, 1.035 mmol) and stirred for 5 h. EtOAc was added to the reaction mixture (20 mL) and 10% NH4OH (15 mL) was added drop wise. The organic layer was separated, dried over sodium sulfate and evaporated. Purification of the crude by flash chromatography over silica gel (DCM/7N NH3 in MeOH 9/1) afforded the title compound (56 mg, 38%).
Reaction SMILES: [CH2:1]([O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25]C(C)(C)C)=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].FC(F)(F)C(O)=O.O>ClCCl>[CH2:1]([O:21][CH:22]([CH2:30][CH3:31])[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (19.6 g, 45.5 mmol) was dissolved in dichloromethane (200 mL) and placed under nitrogen. Trifluoroacetic acid (50 mL) was added and the reaction mixture was stirred at room temperature for one hour. Water was added and the aqueous phase was extracted twice with dichloromethane. The combined organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was subjected to flash chromatography on silica gel using increasingly polar mixtures of heptane, ethyl acetate and formic acid (90:10:1→80:20:1) as eluent. Concentration of the appropriate fractions afforded 12.1 g (71% yield) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3): δ 0.90-1.00 (m, 6H), 1.50 (m, 2H), 1.70 (m, 2H), 1.80 (m, 2H), 2.10 (m, 4H), 2.80-2.90 (m, 8H), 3.50 (m, 1H), 3.60 (m, 1H), 3.75 (t, 1H), 5.30-5.50 (m, 10H); MS (electro spray): 373.2 [M-H]−.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[O:9])[S:6][CH:7]=1)[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)[CH3:2]
Reactant: CCc1csc(C=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCc1csc(CO)c1
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
4-Ethyl-2-thiophenecarbaldehyde (1 g, 7.13 mmol) dissolved in methanol (7 ml) was added with sodium borohydride (135 mg, 3.57 mmol) under ice cooling, stirred for 10 minutes and then further added with sodium borohydride (150 mg, 3.96 mmol) at 0° C. After the reaction solution was stirred under ice cooling for 30 minutes, the reaction was stopped with saturated aqueous ammonium chloride and the reaction solution was extracted with chloroform. The organic layer collected was dried over magnesium sulfate and concentrated under reduced pressure to obtain 1 g (100%) of the title compound without purification.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[CH:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])[NH:17][C:16](=[O:25])[N:15]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:14]3=[O:31])[N:7]=1)=[O:5])C.[CH3:32][NH2:33]>CO.C(O)C>[CH3:32][NH:33][C:4]([C:6]1[N:10]=[CH:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[C:21]([F:22])([F:24])[F:23])[NH:17][C:16](=[O:25])[N:15]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:14]3=[O:31])[N:7]=1)=[O:5]
Reactant: CCOC(=O)c1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n1
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNC(=O)c1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 86 %

Procedure:
A solution of 150 mg (0.324 mmol) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester in 0.8 ml of methanol is treated with 0.40 ml (3.24 mmol) of a ˜8M methylamine solution in ethanol. The mixture is stirred for 22 hours at room temperature and then concentrated in vacuo. The crude product is taken up in water and the pH of the solution is adjusted to 3 with 1 M aqueous HCl solution and the mixture is stirred for 3 hours at 0° C. The crystals are filtered, washed with cold water and dried in vacuo to give 124 mg (86%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid methylamide as white crystals, m.p. 257-260° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[CH:19][CH:18]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([C:16]([F:15])([F:28])[F:29])=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(C(F)(F)F)cc3)nc2n(CC)c1=O
Yield: 49.3 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.20 g (11.2 mmol) of 5,6-diamino-1,3-diethyluracil and 2.66 g (12.3 mmol) of 4-trifluoromethyl-cinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.09 g (yield 49%) of Compound 135 as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.P(=O)(O)(O)O.[CH2:18]=[CH:19][CH:20]=[CH2:21]>C1C=CC=CC=1>[CH3:18][CH:19]1[O:1][C:2]2[C:3](=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:21][CH2:20]1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: C=CC=C
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CC1CCc2c(ccc3[nH]c(=O)ccc23)O1
Temperature: 80 °C
Yield: 34.9 %

Procedure:
6-hydroxyquinoline-2-one (481 mg) and orthophosphoric acid (0.55 ml) were dissolved in 5 ml of benzene, and thereto was added dropwise with stirring 297 mg of butadiene dissolved in 5 ml of benzene. The resulting mixture was heated under reflux at 80° C. for 12 hours. The reaction liquid was poured into ice-cold water and extracted with 100 ml of ethyl acetate. The extracted liquor was washed with water and the ethyl acetate solution was dehydrated by addition of anhydrous sodium sulfate and filtered. The solvent in the filtrate was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to give 224 mg of white needle-like crystals.
Reaction SMILES: N1C2C(=CC=CC=2)C=[CH:2]1.C[C@]12C3C=C(OC(NC)=O)C=CC=3N(C)[C@H]1N(C)CC2.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][C:46]=1[CH:47]([CH3:49])[CH3:48])[NH:43][CH:42]=[CH:41]2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([Mg]Br)C.CI>C1COCC1>[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][C:46]=1[CH:47]([CH3:49])[CH3:48])[NH:43][CH:42]=[C:41]2[CH3:2])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)c1cc2[nH]ccc2cc1OCc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: CNC(=O)Oc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c[nH]c2cc(C(C)C)c(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The methylation carried out in this step follows the procedure for indole alkylation reported by Marino et al. in “The Enantioselective Synthesis of (−) Physostigmine Via Chiral Sulfoxides”, J. Am. Chem. Soc. (1992), 114, 5566-5572. 5-Benzyloxy-6-isopropyl-1H-indole (0.855 g, 3.22 mmol) was dissolved in 20 mL of dry THF, and the resulting solution was cooled in an ice bath. Ethyl magnesium bromide (4.9 ml, 4.9 mmol in ether) was added dropwise to the solution, and the solution was then stirred for 4 hours at room temperature. Methyl iodide (1.42 g, 10 mmol) was then added, and stirring was continued for an additional 18 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified with flash chromatography (ethyl acetate/hexanes=1/9) to yield 325 mg of 5-benzyloxy-6-isopropyl-3-methyl-1H-indole Mass Spec (M+H): 280.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:25][S:26]([O:11][C@H:10]([CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:28])=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)C1CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)C1CCOCC1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethanol (3.29 g, 12.7 mmol) in 60 mL of CH2Cl2 was cooled to 0° C. under N2. Triethylamine (3.58 mL, 25.7 mmol) was then added followed by methanesulfonyl chloride (2.57 g, 17.0 mmol) and DMAP (61 mg, 0.50 mmol) and the reaction mixture was stirred and allowed to warm to ambient temperature overnight. The reaction mixture was treated with saturated aqueous NaHCO3 solution and the layers were separated. The organic portion was washed successively with aqueous 3.5% NaH2PO4 solution (2×), H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4.29 g of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethyl methanesulfonate as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:29]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=[S:32])[NH:7][C:6]=2[CH:29]=1
Reactant: Cc1cc2c(cc1C)N(C(=O)CN1CCN(CCO)CC1)c1ncccc1C(=O)N2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1cc2c(cc1C)N(C(=O)CN1CCN(CCO)CC1)c1ncccc1C(=S)N2

Procedure:
In the manner given in Example 1, 8,9-dimethyl-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dimethyl-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].[NH2:16][C:17]1[C:33]([Cl:34])=[CH:32][C:20]([C:21]([NH:23][C@H:24]2[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]2[O:30][CH3:31])=[O:22])=[C:19]([O:35][CH3:36])[CH:18]=1.C(=O)([O-])O.[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[NH2:16][C:17]1[C:33]([Cl:34])=[CH:32][C:20]([C:21]([NH:23][C@H:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][N:4]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][C:5]3=[O:15])[CH2:26][C@H:25]2[O:30][CH3:31])=[O:22])=[C:19]([O:35][CH3:36])[CH:18]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)C[C@H]1OC

Procedure:
A mixture of 3.8 parts of 3-(2-chloroethyl)-2(1H), 4(3H)-quinazolinedione, 4.7 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 1.7 parts of sodium hydrogen carbonate, 0.1 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone was stirred and refluxed for 24 hours. Water was added to the reaction mixture. The precipitated product was filtered off and crystallized from N,N-dimethylformamide and a small amount of water, yielding 3.3 parts of cis-4-amino-5-chloro-N-[1-[2-(1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl)ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 270.8° C. (compound 142).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:18])([CH2:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][CH3:16])[C:4](=[O:19])[C:3]=1[C:20]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([NH:30]C(=O)OC(C)(C)C)=[CH:29][C:23]=2[S:22](=[O:39])(=[O:38])[N:21]=1.[ClH:40]>O1CCOCC1>[ClH:40].[NH2:30][C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:20]([C:3]3[C:4](=[O:19])[C:5]([CH3:18])([CH2:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][CH3:16])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[N:21][S:22](=[O:39])(=[O:38])[C:23]=2[CH:29]=1
Reactant: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 88 %

Procedure:
A solution of Example 43E (152 mg, 0.270 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give 119 mg (88%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.45 (m, 1H) 0.66 (m, 6H) 0.92 (m, 2H) 1.12 (m, 2H) 1.57 (s, 3H) 2.15 (m, 2H) 7.01 (m, 2H) 7.46 (d, J=8.82 Hz, 1H) 7.54 (m, 1H) 7.77 (m, 2H) 8.16 (m, 1H) 13.57 (s, 1H); MS (ESI+) m/z 454 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: C[C@H](O)C(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Cl[CH2:27][CH:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:29].Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:27][CH:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH3:29])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Reactant: CC(CCl)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(C)N4CCCC4)cc3)oc2c1

Procedure:
40 mg (119 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 23.5 mg (128 μmol) 1-(2-chloro-1-methylethyl)pyrrolidine×HCl, 50 mg (362 μmol) potassium carbonate and 2 ml DMF are heated together for 6 h to 80° C. Then the mixture is extracted with 10% sodium carbonate solution and EA. The org. phase is washed with sat. saline solution, dried on sodium sulphate and then the solv. is totally eliminated i.V. The residue is separated by semipreparative HPLC-MS. (xBridge, MeOH/H2O+TFA)