Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].[C:12]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH3:16])(=[O:14])[CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][S:23]([C:20]1[CH:19]=[CH:18][C:17]([N:15]([C:12](=[O:14])[CH3:13])[CH3:16])=[CH:22][CH:21]=1)(=[O:25])=[O:24]
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
2-Indanylamine hydrochloride (9.68 g, 57.1 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (12.84 g, 51.9 mmol) prepared in Preparative Example 12 and sodium acetate (18.73 g) in ethanol (100 ml). The obtained mixture was stirred at room temperature for 3 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-(2 indanyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a white crystal (16.92 g, 95%). Ethanol (80 ml) and 1N aqueous sodium hydroxide (80 ml) were added to the white crystal. The obtained mixture was heated under reflux overnight, acidified with 1N aqueous hydrochloric acid, adjusted to pH 8 with sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to precipitate a crystal. This crystal was recovered by filtration and washed with ether to give the title compound as a white crystal (6.79 g, 46%).
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH:10]=[CH2:11])[O:8][C:7](=[O:12])[NH:6]1)[CH:2]([CH3:4])[CH3:3].B1C2CCCC1CCC2.C1C[O:25]CC1>>[CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][OH:25])[O:8][C:7](=[O:12])[NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: C=C[C@@H]1OC(=O)N[C@H]1CC(C)C
Agent: B1C2CCCC1CCC2
Product: CC(C)C[C@@H]1NC(=O)O[C@H]1CCO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 0° C. solution of 4(S)-isobutyl-5(S)-vinyl-2-oxazolidinone (4.7 g, 0.028 mole) in THF (20 mL) was added 9-BBN [9-borabicyclo(3.3.1)nonane, 75 mL, 0.0375 mole in THE] by dropwise addition. After stirring for 5 hours at room temperature, the reaction was quenched by the addition of water (1 mL). A solution of NaOH (6.7 g) in water (21 mL) was then added followed by careful addition of H2O2 (18 mL of 30%). The resulting mixture was heated at 65° C. for 1 hour, the THF was partially evaporated and the residue was distributed between ethyl acetate and brine solution. The organic phase was washed with brine solution and dried over MgSO4. Evaporation of the solvent gave a residual oil which was flash chromatographed on silica get eluting with 5% MeOH in methylene chloride. The pure fractions were combined and evaporated to give 4.62 g of 4(S)-isobutyl-5(S)-(2-hydroxyethyl)-2-oxazolidinone. A solution of this material (3.95 g, 0.021 mol) and triethylamine (3.2 g, 0.032 mol) in methylene chloride (40 mL) was cooled to 0° C. and treated by dropwise addition with mesyl chloride (2.89 g, 0.025 mol). After stirring for 1 hour at 0-5° C., the methylene chloride was washed successively with 0.5 N HCl, aqueous NaHCO3 and brine solution. The organic solution was dried and evaporated to a solid product. Recrystallization from hexane/methylene chloride gave 3.9 g (70%) of product, m.p. 99°-100° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:26][CH:27]([NH2:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:32][CH:27]([CH3:26])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O
Product: CC(NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O)C(C)(C)C
Yield: 57 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.225 g, 0.56 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in DCM, washed twice with 1N aqueous HCl and once with water. The organic phase was dried (sodium sulfate) and concentrated. The residue was crystallised from ethyl acetate/heptane 1:4 to give 146 mg (57%) of the title compound. Mp 184.5-188.5° C. 1H NMR (200 MHz, CDCl3): δ=0.9 (s, 9H), 1.03 (d, 3H), 3.0 (m, 1H), 7.52 (s, 2H), 7.68 (s, 1H); EI SP/MS: 457 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH2:26])[CH2:10][C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH2:10][C:9]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@H]2CC[C@H](n3cnc4c(N)ncnc43)[C@@H]1C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@@H]3CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A 100 ml two-necked round-bottomed flask was loaded with 4.96 g of Boc-A lactams [sic] 15e (13.3 mmol) and 60 ml of dry CH2Cl2. 5.35 ml of dry pyridine (66.5 mmol) were then added, followed by 1.59 g of DMAP (1.3 mmol). After cooling to 0° C., 5.4 ml of 4-methoxybenzoyl chloride (39.9 mmol) were added dropwise and the mixture was stirred at 0° C. for 15 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 22 h. The reaction mixture was then again cooled to 0° C. and 35 ml of MeOH were added dropwise. After 30 min at 0° C., 80 ml of a saturated solution of NH3 in MeOH were added dropwise. A white precipitate was formed, which dissolved after complete addition of the solution. After 30 min, the ice bath was removed and the reaction was stirred at room temperature for a further 2 h. The solvent was then removed under reduced pressure and the resulting residue was dissolved in 200 ml of CH2Cl2. The solution was washed successively with 150 ml of saturated NaHCO3 solution and aqueous citric acid solution (20%, 2×100 ml), washed [sic] over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by means of chromatography (5.2×18 cm silica gel; eluent: EtOAc/MeOH 40:3) to afford 5.93 g of 15f (88%).
Reaction SMILES: C(O)C.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7].[Sn].[CH2:15](Br)[CH:16]=[CH2:17]>O>[CH2:17]([CH:12]([OH:13])[C@@H:10]([C@H:8]([C@@H:6]([CH2:5][OH:4])[OH:7])[OH:9])[OH:11])[CH:16]=[CH2:15]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: C=CCBr
Agent: [Sn]
Solvent: CCO
Solvent: O
Product: C=CCC(O)[C@H](O)[C@@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
A five liter three-necked round bottom flask, equipped with heating mantle, stirrer, nitrogen inlet, and condenser, was charged with 1.8 liters of ethanol, 0.3 liters of water, 300 g (2.00 mole) of D-xylose, 242 g (2.04 mole) of tin powder (−325 mesh), and 242 g (2.00 mole) of allyl bromide. The mixture was stirred and slowly heated to reflux—a significant exotherm and gas evolution was observed at 60° C. The gray suspension was stirred at reflux for three days, in which time the reaction mixture turned an orange/brown color. Heat was removed and the mixture was allowed to cool to room temperature. The reaction was neutralized to pH=7 by adding approximately 400 ml of 5M NaOH aqueous solution. The suspension was filtered to remove solids, and the yellow solution was decolorized with multiple treatments of activated carbon. The activated carbon was removed by filtration, and the solvent was removed by rotary evaporation to isolate a white syrup. Typical yield was 320 g. 1H NMR (300 MHz, D2O, ppm): 2.33-2.39 (m, 2H), 3.55-3.89 (m, 6H), 5.14-5.23 (m, 2H), 5.89 (m, 1H). The syrup was used without further purification.
Reaction SMILES: BrC1C=CC(O[CH2:11][CH2:12][O:13][Si:14]([C:17](C)(C)C)([CH3:16])[CH3:15])=C(C=1)C=O.C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.[CH2:40]([N:42](CC)CC)C.C(Cl)(=O)C>>[CH3:15][Si:14]([CH3:17])([CH3:16])[O:13][C:12](=[CH2:11])[N:42]=[CH2:40]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1C=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Product: C=NC(=C)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 1b, 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (17.25 g, 48 mmol) prepared in example 130a was reacted with 1,1,1,3,3,3-hexamethyldisilazane (8.28 g, 48 mmol), n-butyllithium (2.5 M, 19.2 mL, 48 mmol), trimethylsilyl chloride (6.07 mL, 48 mmol), triethylamine (8.7 mL, 62.5 mmol) and acetyl chloride (4.53 mL, 62 mmol) to give 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].CS[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[C:7]=1[N:14]=[O:15]>CN(C=O)C>[NH:2]([C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[C:7]=1[N:14]=[O:15])[NH2:3]
Reactant: CSc1nc(N)nc(N)c1N=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: NNc1nc(N)nc(N)c1N=O
Reaction time: 8 h

Procedure:
Hydrazine hydrate (55% solution, 14.5 mL) was added rapidly to a suspension of (12.0 g; 64.9 mmol) of 6-Methylthio-5-nitroso-pyrimidine-2,4-diamine 2 in DMF at room temperature. The mixture was allowed to stir overnight and then the bright pink mixture was filtered and the solid washed several times with DMF followed by ether and then air dried to give 9.53 g of 6-Hydrazino-5-nitroso-pyrimidine-2,4-diamine as bright pink solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[CH2:13]>C(OCC)C>[C:2]1([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cccc(Br)c1
Reactant: Brc1ccccc1
Solvent: CCOCC
Product: C=Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
The liquid temperature was increased until refluxing took place and then a solution of 7.37 g (0.07 mole) of bromobenzene in diethyl ether (70 ml) was gradually added dropwise taking 30 minutes. After completion of the dropwise addition, it was kept as such for 1 hour under reflux. The reaction solution was cooled to room temperature and it was added at room temperture to a solution of 6.51 ml (0.05 mole) of m-bromostyrene and 0.32 g (0.6 m mole) of a nickel chloride-(1,3-diphenyl phosphino propane) complex in diethyl ether (100 ml). After completion of the dropwise addition, refluxing was continued for 4 hours. The reaction solution was poured into 500 ml of ice water and the pH was adjusted to be weakly acidic. Extraction with hexane was undertaken and, through washing, drying, removal of the solvent by distillation and purification by the silica gel column chromatography, 7.32 g of m-phenyl styrene (yield 80%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH3:38])[CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH3:38])[CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1
Reactant: CN(Cc1nccs1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Solvent: CC(=O)O
Solvent: O
Product: CN(Cc1nccs1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Reaction time: 48 h

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[methyl(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide was dissolved in acetic acid (8 mL) and water (2 mL). The reaction mixture was left to stir 2 days. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[methyl(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.3469 g). LCMS: (M+H)+=486.1.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[ClH:15].[CH2:16](O)[CH3:17]>>[ClH:15].[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: COc1cccc(C(N)CC(=O)O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC(N)c1cccc(OC)c1

Procedure:
Corresponding to Example 1b, 60 g of (8a) were treated with hydrochloric acid in ethanol. A white, crystalline product was obtained (yield: 75 g).
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].Br[C:28]1C=C2C(CN(C3(C(OC)=O)CCCC3)C2=O)=C[CH:29]=1>>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([C:2]4([C:3]([O:5][CH3:6])=[O:4])[CH2:1][CH2:29][CH2:28][CH2:7]4)[C:9]3=[O:26])=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Reactant: COC(=O)C1(N2Cc3ccc(Br)cc3C2=O)CCCC1
Product: COC(=O)C1(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)CCCC1
Yield: 76 %

Procedure:
The compound of example 526 was prepared analogous to compound of example 514 by reaction of the compound of example 341 and
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[N:43]1([CH2:48][CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][N:45]=[CH:44]1>CC(N(C)C)=O>[N:43]1([CH2:48][CH2:49][CH2:50][NH:51][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])(=[O:30])=[O:31])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: NCCCn1ccnc1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 3-imidazol-1-yl-propylamine (40 mg, 2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:15]2[S:25][C:18]3[N:19]([CH3:24])[C:20]([CH:22]=O)=[CH:21][C:17]=3[CH:16]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[C:4]([C:15]2[S:25][C:18]3[N:19]([CH3:24])[C:20]([CH2:22][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][C:17]=3[CH:16]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: C1CCNC1
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(C=O)n(C)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(CN3CCCC3)n(C)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To solution of methyl 5-ethyl-6-(5-formyl-6-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-2-methoxynicotinate (49.4 mg, 0.14 mmol) in dichloroethane (1.5 mL) was added pyrrolidine (20 μL, 0.24 mmol) followed by AcOH (15 μL, 0.25 mmol). After stirring at room temperature for 10 min NaBH(OAc)3 (60 mg, 0.28 mmol) was added. Reaction was stirred at room temperature overnight and then quenched with NaHCO3 solution (aqueous saturated, 5 mL). Product was extracted with DCM (3×7 mL). Organic phase was dried over Na2SO4 and solvent was concentrated. Product was purified by column chromatography (MeOH/DCM, 0-5% gradient). Methyl 5-ethyl-2-methoxy-6-(6-methyl-5-(pyrrolidin-1-ylmethyl)-6H-thieno[2,3-b]pyrrol-2-yl)nicotinate (49.7 mg) was obtained in 86% yield. LC-MS 343.1 [M-71+H]+, RT 1.00 min.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[CH3:16][NH2:17].[BH4-].[Na+].O>CCO>[CH3:16][NH:17][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(Oc2cncnc2)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNCc1ccc(Oc2cncnc2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(Pyrimidin-5-yloxy)benzaldehyde (0.344 g, 1.7 mmol) was stirred with 33% methylamine in EtOH (30 mL) at reflux for 3 hours and then concentrated. The residue was dissolved in MeOH and treated with sodium borohydride (0.195 g, 5.2 mmol) over 1 hour and stirred for a further 1 hour. Water was added and the product was extracted three times with EtOAc. The organic phases were combined, washed with brine, dried and concentrated to give 0.267 g (100%) of product that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[C:27]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35](O)=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[C:22]([CH3:42])[NH:23]2>>[F:18][C:19]1[C:27]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]4)=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[C:22]([CH3:42])[NH:23]2
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (432 mg, 1.77 mmol) was reacted with 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (500 mg, 1.47 mmol), (prepared as described for the starting material in Example 7). The product was purified by column chromatography, eluting with 2%-5% methanol/methylene chloride to give tert-butyl 4-[3-(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline-7-yloxy)propyl]piperazine-1-carboxylate (582 mg, 70%).
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][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[CH:23]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:23]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1
Reactant: CCOC([O-])[O-]
Reactant: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NCc3nncn3-c3ccc(Cl)cc32)cc1

Procedure:
To a suspension of 1.6 parts of 7-chloro-2-hydrazino-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine prepared in Example 2 in 50 parts by volume of ethanol is added 3.0 parts of ethyl orthoformate, and then 0.5 part by volume of concentrated sulfuric acid is added dropwise with stirring. The whole mixture is stirred for a while and then neutralized with an aqueous slution of sodium bicarbonate, followed by evaporaton of the solvent. Water is added to the residue, whereby 8-chloro-6-(p-methoxyphenyl)-4H-s-triazolo (4,3-a) (1,4) benzodiazepine is yielded as crystals. Recrystallization from acetone and and then from ethyl acetate yields pale yellow flakes melting at 216° C to 217° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH3:7])[CH2:5][OH:6].C(Cl)(Cl)(Cl)Cl.ClC(Cl)(Cl)C(=N)O[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>FC(F)(F)S(O)(=O)=O.C1CCCCC1>[CH2:18]([O:6][CH2:5][C@H:4]([CH3:7])[C:3]([O:2][CH3:1])=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](C)CO
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: COC(=O)[C@@H](C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
An oven dried 1 L single-necked round bottom flask was equipped with a magnetic stir bar and then charged sequentially with 15.948 g (0.135 mol) of (R)-(-)-methyl-3-hydroxy-2-methylpropanoate, carbon tetrachloride (150 mL), cyclohexane (300 mL), and 35.796 g (0.142 mol) of benzyl 2,2,2-trichloroacetimidate. Trifluoromethanesulfonic acid (0.8 mL; 9.0 mmol) was added to the solution and the resulting mixture was stirred for 16 h at room temperature under an N2 atmosphere. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was redissolved in 150 mL EtOAc and extracted with saturated aqueous NaHCO3 (lxlOO mL). The organic layer was washed with saturated NaCl, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane. The purified fractions were combined and evaporated in vacuo to afford 20.787g of the title compound as an oil. MS (CI): m/e=209 (M+1).