Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].Cl.N1C=CC=C(CC(O)=O)C=1.[C:28]([O:32][C:33]([N:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[CH3:36])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:39]=[CH:38][C:37]([N:35]([C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH3:36])=[CH:45][CH:44]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Agent: Cl
Agent: O=C(O)Cc1cccnc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)cc1
Yield: 69 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.16 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in the same manner as in Reference Example 2 and, instead of 3-pyridylacetic acid hydrochloride, 4-(N-t-butyloxycarbonyl-N-methylamino)benzoic acid which was prepared separately by a conventional method, to obtain 3.10 g of 1-benzyl-4-(4-(N-t-butyloxycarbonyl-N-methylamino) benzoylamino)-5-imidazolecarboxamide (yield 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:29]1(=[O:36])[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[OH:36][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[C:30]=1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C1CCCC(O)=C1C(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
4-Nitrophenylacetic acid (8.1 g, 45 mmol) and then dicyclohexylcarbodiimide (9.7 g, 47 mmol) were added to a dichloroethane (150 ml) suspension of 1,3-cyclohexanedione (5.00 g, 44.6 mmol) at room temperature, after which 4-dimethylaminopyridine (0.27 g, 2.2 mmol) was added and stirring carried out for 1 hour at 60° C. and then further 4-dimethylaminopyridine (0.54 g, 4.4 mmol) added and stirring carried out for 23 hours at 85° C. The dicyclohexylurea was filtered off while the solution was still warm, then the reaction solution washed with dilute hydrochloric acid (50 ml), after which the aqueous layer was extracted with dichloromethane. After drying with anhydrous sodium sulphate, the solvent was distilled off and separation and purification performed by column chromatography. When recrystallization was performed from ethanol, 3-hydroxy-2-(4-nitrophenylacetyl)-2-cyclohexenone (8.2 g, 67%) was obtained as yellow crystals. Tetrahydrofuran (100 ml), methanol (35 ml) and concentrated hydrochloric acid (10 ml) were added to the compound obtained (2.00 g, 7.3 mmol), then Pd-C (5%, containing 100% of water, 300 mg) added and the atmosphere replaced by hydrogen. The raw material was consumed in 4 hours and then the hydrogen replaced by argon. The precipitate was filtered off, washed with hot methanol, and the filtrate concentrated. When the solid obtained was recrystallized from ethanol, 2-(4-aminophenylacetyl)-3-hydroxy-2-cyclohexenone hydrochloride (1.3 g, 64%) was obtained. A chloroform (15 ml) solution of the compound (500 mg, 1.77 mmol) obtained was ice-cooled and 2-thiopheneacetyl chloride (0.26 ml, 2.1 mmol) added. Next, pyridine (0.44 ml, 5.5 mmol) was added and stirring carried out for 3 hours. After returning to room temperature, stirring was carried out for 15 hours, then dilute hydrochloric acid added and extraction performed with dichloromethane. The organic layer was dried with anhydrous sodium sulphate, and the solvent distilled off. When recrystallization was performed from ethanol, Compound 4 (245 mg, 37%) was obtained as pale yellow crystals.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[O:8][C:7](=[O:17])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCCC1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:5]([CH2:4][NH:2][CH3:1])=[CH:6][C:7](=[O:17])[O:8]2)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1cc(=O)oc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methylamine in tetrahydrofuran (2M, 1.10 ml) was added to an ice-cooled mixture of 4-bromomethyl-7-methoxycoumarin (0.30 g), potassium carbonate (0.5 g) and dichloromethane (10 ml). The mixture was stirred at room temperature for 2 days then added to an aqueous solution of potassium carbonate. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (eluent 10% methanol in dichloromethane), then crystallised from methanol to give the title compound as a white solid (0.14 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:40])[C@@H:10]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1)[C:11]([NH:13][NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:40])[C@@H:10]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([C:36]([F:37])([F:39])[F:38])[CH:29]=1)[C:11]1[O:26][C:15]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-(methylsulfonyl)benzohydrazide (5.29 g, 8.80 mmol) in CH2Cl2 (250 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (4.64 g, 17.7 mmol), iodine (4.48 g, 17.6 mmol) and Et3N (4.9 mL, 35.2 mmol). The reaction mixture was warmed to room temperature, stirred for 20 minutes and quenched with 10% sodium thiosulfate (100 mL). The organic extract was washed with 10% sodium thiosulfate (100 mL), H2O (100 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a pink foam, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes) to provide the title compound (4.81 g, 94%), which was used directly in the next step.
Reaction SMILES: CON(C)[C:4](=[O:22])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1.[CH:24]([Mg]Br)=[CH2:25].Cl>O1CCCC1>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)[C:4](=[O:22])[CH:24]=[CH2:25])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A solution of N-methoxy-N-methyl-2-[4-(methylsulfonyl)phenyl]-3-(tetrahydrofuran-2-yl)propanamide (1.68 g) in tetrahydrofuran (19.7 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 19.7 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 3 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (930 mg, yield 61%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 309 (MH+).
Reaction SMILES: [CH2:1]([Si:4]([CH2:30][CH:31]=[CH2:32])([CH2:27][CH:28]=[CH2:29])[CH2:5][CH2:6][CH2:7][Si:8]([CH2:14][CH2:15][CH2:16][Si:17]([CH2:24][CH:25]=[CH2:26])([CH2:21][CH:22]=[CH2:23])[CH2:18][CH:19]=[CH2:20])([C:10]([CH3:13])([CH3:12])[CH3:11])[OH:9])[CH:2]=[CH2:3].[CH2:33](N(CC)CC)C.C(OCC)C.Cl>C1COCC1>[CH2:21]([Si:17]([CH2:18][CH:19]=[CH2:20])([CH2:24][CH:25]=[CH2:26])[CH2:16][CH2:15][CH2:14][Si:8]([CH2:7][CH2:6][CH2:5][Si:4]([CH2:1][CH:2]=[CH2:3])([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])([C:10]([CH3:11])([CH3:12])[CH3:13])[O:9][CH3:33])[CH:22]=[CH2:23]
Reactant: CCN(CC)CC
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Si](O)(CCC[Si](CC=C)(CC=C)CC=C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[Si](CC=C)(CC=C)CCC[Si](CCC[Si](CC=C)(CC=C)CC=C)(OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 37 h
Yield: 33 %

Procedure:
Bis{3-(triallylsilyl)propyl}tert-butyl silanol (29) (10.3 mg, 0.02 mmol) was dissolved in distilled THF, two equivalents of Meerwein Reagent (Me3OBF4) and two equivalents of triethylamine were added dropwise and stirred at room temperature for 37 hours. To the reacted mixture, diethyl ether was added then 1N hydrochloric acid was added then the obtained water layer was extracted with diethyl ether. The collected organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure, obtaining bis{3-(triallylsilyl)propyl}(tert-butyl)methoxysilane (30) represented by the following chemical reaction equation (yield: 3.5 mg, yield (%): 33%).
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:5]=2[CH:4]=1)=[O:2].I[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH2:31])[N:24]([CH:32]([CH3:34])[CH3:33])[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]([CH3:34])[CH3:33])[N:23]=[C:22]([C:8]3[S:7][C:6]4[CH:19]=[CH:20][C:3]([CH:1]=[O:2])=[CH:4][C:5]=4[CH:9]=3)[C:30]=12
Reactant: CC1(C)OB(c2cc3cc(C=O)ccc3s2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cc3cc(C=O)ccc3s2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 45 %

Procedure:
A solution of 5-Formylbenzo[b]thiophene-2-boronic acid pinacol ester (31 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA42 (15.2 mg, 45% yield). ESI-MS (M+H)+ m/z calcd 338.1, found 338.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>CC(C)=O>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:13])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 29.2 %

Procedure:
7-methoxyquinoxalin-2(1H)-one (Intermediate 148, 300 mg, 1.70 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.56 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.4 mmol) as described for Intermediate 2. Chromatography on silica gel with 25% acetone in hexanes gave 200 mg (29%) of the product as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22](O)([CH2:25][CH3:26])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1.S(=O)(=O)(O)O.C(O)(=O)C.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.[OH-].[Na+]>O>[CH2:25]([C:22]([C:4]1[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1)=[CH:23][CH3:24])[CH3:26]
Reactant: CCC(O)(CC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC=C(CC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Yield: 101.4 %

Procedure:
A mixture of 3-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pentan-3-ol (0.041 g, 0.122 mmol), concentrated sulfuric acid (0.055 g, 0.56 mmol) and acetic acid (0.136 g, 2.27 mmol) was heated to reflux for 1 hour, cooled, diluted with water, basified to pH10 with 2 N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to dryness to give 43 mg of the title compound as a clear oil. The oil was purified through silica gel column chromatography to give 40 mg of the title compound as a white solid, mp 59-61° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]([CH2:19][C:20](OCC)=[O:21])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]1[CH:19]=[C:20]([OH:21])[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=2)[N:1]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc2nc(-c3ccccc3F)cc(O)c2c1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
Ethyl p-aminophenylacetate (8 g), ethyl 2-fluorobenzoylacetate (10 g) and p-toluenesulfonic acid (1 g) were dissolved into benzene (150 ml) and, providing Dean Stalk dehydrating apparatus placed molecular sieve (MS 4 angstroms) therein, the solution was refluxed for 4.5 hours under heat. Solvent was distilled off under reduced pressure and water was added to the residue, which was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. After diphenyl ether (60 ml) was added to the residue, the mixture was stirred at 240° to 250° C. for 30 minutes under heat. After cooling, ether was added and the crystals deposited were collected by filtration to obtain crude ethyl 2-(2-fluorophenyl)-4-hydroxyquinoline-6-acetate (9.5 g). After phosphorus oxychloride (40 ml) was added thereto, the mixture was refluxed for 2 hours under heat. After cooling, this was thrown into ice and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain ethyl 4-chloro-2-(2-fluorophenyl)quinoline-6-acetate (9.2 g). This was dissolved into ethanol (200 ml) and, after 10% palladium carbon (1 g) was added, hydrogenation was conducted at a hydrogen pressure of 40 kg/cm2 and at 80° C. Catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by means of silica gel column chromatography (development solvent: methylene chloride) to obtain aimed product (3.7 g) as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH2:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:20]1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32]([NH:1][C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([C@@H:6]4[CH2:16][C@@H:7]4[CH2:8][O:9]3)=[CH:4][CH:3]=2)(=[O:33])=[O:34])[CH2:20]1)[CH3:18]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@H]2C[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.257 g) in DCM (10 mL) and pyridine (5 mL) was treated with a solution of 2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 96, 0.36 g) in DCM (10 mL) and the mixture was stirred at room temperature overnight. The resultant mixture was evaporated to dryness and the residue was re-dissolved in DCM, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10%, then flushed with 100% methanol to give methyl (1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.13 g) as a gum.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3=[CH:13][S:14][CH:15]=[C:10]3[C:9](SC)=[N:8][C:7]=2[CH:18]=1.O.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3=[CH:13][S:14][CH:15]=[C:10]3[C:9]([N:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]3)=[N:8][C:7]=2[CH:18]=1
Reactant: OCCN1CCNCC1
Reactant: CSC1=Nc2cc(SC)ccc2Nc2cscc21
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc2c(c1)N=C(N1CCN(CCO)CC1)c1cscc1N2

Procedure:
A solution of 7,10-bis(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-(2-hydroxyethyl)-piperazine and glacial acetic acid is heated at 140°-160° C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C@H:39]([NH2:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:41][C@@H:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH3:40])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cccc([C@@H](C)N[C@H]2CCN(Cc3ccccc3)C2)c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
To a solution of 8.0 g of (R)-1-benzyl-3-pyrrolidinol and 16.5 ml of diisopropylethylamine dissolved in 400 ml of methylene chloride was added dropwise a solution of 13.4 g of anhydrous trifluoromethanesulfonic acid in 50 ml of a methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., then, a solution of 9.88 g of (R)-1-(3-methoxyphenyl)ethylamine in 100 ml of methylene chloride was added dropwise to the mixture at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=1:0→50:1) and NH silica gel column chromatography (hexane:ethyl acetate=25:1→10:1) to obtain 3.98 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine. MS•APCI (m/z): 311 [M+H]+ (2) To a solution of 3.67 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine dissolved in 100 ml of methanol were added 830 mg of palladium hydroxide and 8.85 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 3 days. Palladium hydroxide was removed, and the solvent was evaporated. To the residue was added methanol, and the resulting precipitates were collected by filtration, washed with methanol and dried to obtain 1.14 g of (S)-3-[(R)-1-(3-methoxyphenyl)-ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.001).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[S:11][C:12]([CH:15]=[O:16])=[CH:13][N:14]=1)=[O:4].[CH3:18][C@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](O)=[O:21].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:15]([C:12]1[S:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][N:23]([C@@H:19]([CH3:18])[CH:20]=[O:21])[C:24](=[O:25])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH3:17])=[N:14][CH:13]=1)=[O:16]
Reactant: C[C@H](N)C(=O)NCCCNc1ncc(C=O)s1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: C[C@H](NN(C(=O)OC(C)(C)C)[C@@H](C)C=O)C(=O)NCCCNc1ncc(C=O)s1
Yield: 66.2 %

Procedure:
Following the procedure as described in Example 24, except using the material from Example 70 (260 mg, 0.790 mmol), N-alpha-t-BOC-L-Alanine (161 mg, 0.853 mmol), 1-hydroxy-7-azabenzotriazole (53.7 mg, 0.395 mmol), CH2Cl2 (15 mL), N-methylmorpholine (178 μlit, 1.62 mmol), and EDC (182 mg, 0.948 mmol), 223.5 mg (66.2%) of the title compound is obtained as an off white solid. Purification is done by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% ACN over 10 column volumes, with a hold at 100% ACN for 15 column volumes. LC/MS (Condition A): ret. T=2.59 min, (M+H)+ 428.23.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17]
Reactant: Nc1ccccc1F
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1F
Temperature: 140 °C
Yield: 51.7 %

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (1.50 g, 6.46 mmol) is suspended in xylenes (7.5 mL) and 2-fluoro-phenylamine (6.24 mL, 64.6 mmol) is added. The reaction mixture is stirred at 140° C. under N2. After stirring for 6 days, the reaction is complete. The reaction mixture is cooled to room temperature and diluted with methylene chloride and filtered through a silica gel plug eluting with methylene chloride (1 L) to give an orange filtrate. The filtrate is concentrated to dryness and then triturated with diethyl ether to yield a bright yellow solid. The trituration is repeated. The yellow solid is collected to yield 1.08 g (52%) of the pure desired product. MS APCI (−) m/z 322 (M−1) detected.