Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:10]=[C:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[C:7]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[C:4]=1[CH:5]=O.[BH3-]C#N.[Na+]>CO>[NH2:2][C:3]1[N:10]=[C:9]([C:11]2[C:12]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][CH:14]=[CH:15][C:16]=2[OH:17])[CH:8]=[C:7]2[C:4]=1[CH2:5][N:28]1[CH2:27][CH:26]2[CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nc(-c2c(O)cccc2OCc2ccccc2)cc(C2CCCNC2)c1C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Nc1nc(-c2c(O)cccc2OCc2ccccc2)cc2c1CN1CCCC2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cold (0° C.) solution of 2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinaldehyde hydrochloride (0.100 g, 0.227 mmol) in methanol was added NaBH3CN (0.040 mL, 0.682 mmol) under an argon atmosphere. The mixture was stirred at room temperature for 12 hrs and concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The separated organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 2-(6-amino-5,9-diazatricyclo[7.3.1.02,7]trideca-2,4,6-trien-4-yl)-3-(benzyloxy)phenol as a white solid.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:14]([C:19]([OH:21])=O)[CH2:15][CH:16]([CH3:18])[CH3:17].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[NH:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:14]([C:19]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:21])[CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: Nc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
8.43 g (44.0 mmol) of EDCl was added to 100 ml of THF solution of 9.97 g (40.0 mmol) of Boc-Leu-OH (manufactured by Tokyo Chemical Industry Co., Ltd), 3.65 ml (40.0 mmol) of aniline and 4.60 g (40.0 mmol) of HO-Su(hydroxysuccinimide), followed by stirring for 8 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), the organic layer was dried over sodium sulfate. After the drying agent was separated by filtration, the filtrate was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=9/1 to 2/1 (volume ratio)), thereby obtaining 5.43 g of the product with a yield of 44.3%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[C:5]([C:12]([OH:14])=O)=[CH:6][NH:7]2.[NH2:16][C:17]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]3[CH2:30][CH2:31][CH:26]2[CH2:27][CH2:28]3)=[CH:21][C:18]=1[C:19]#[N:20].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:29]12[N:25]([C:22]3[CH:23]=[CH:24][C:17]([NH:16][C:12]([C:5]4[C:4](=[O:15])[C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[CH3:1])[NH:7][CH:6]=4)=[O:14])=[C:18]([C:19]#[N:20])[CH:21]=3)[CH:26]([CH2:31][CH2:30]1)[CH2:27][CH2:28]2
Reactant: N#Cc1cc(N2C3CCC2CC3)ccc1N
Reactant: Cc1cccc2[nH]cc(C(=O)O)c(=O)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: Cc1cccc2[nH]cc(C(=O)Nc3ccc(N4C5CCC4CC5)cc3C#N)c(=O)c12
Temperature: 100 °C
Yield: 49.3 %

Procedure:
To a solution of 5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 35 (162 mg, 0.80 mmol) and 2-amino-5-(7-azabicyclo[2.2.1]heptan-7-yl)benzonitrile 23 (170 mg, 0.80 mmol) in 2-methyltetrahydrofuran (1.5 mL) was added propyl phosphonic acid cyclic anhydride (50% solution in ethyl acetate, 949.5 μL, 1.605 mmol) and pyridine (126 mg, 129 μL, 1.60 mmol). The reaction was capped and heated at 100° C. for 65 min with microwave irradiation. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), and quenched with saturated Na2CO3 solution (6 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-35% ethyl acetate in dichloromethane) provided N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-cyanophenyl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (157 mg, 49% yield). LC/MS m/z 399.3 [M+H]+, retention time 1.47 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400.0 MHz, DMSO-d6) δ 12.77 (s, 1H), 12.75 (s, 1H), 8.77 (s, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.64-7.60 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.27 (dd, J=2.8, 9.1 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 4.32 (s, 2H), 2.91 (s, 3H), 1.65 (d, J=7.2 Hz, 4H), 1.42 (d, J=6.8 Hz, 4H).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:19]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CCC(=O)Nc1nccc2cc[nH]c12
Product: CCC(=O)Nc1nccc2c(C(=O)c3c(F)cccc3Cl)c[nH]c12

Procedure:
N-[3-(2-Chloro-6-fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]propanamide was synthesized using N-(1H-pyrrolo[2,3-c]pyridin-7-yl)propanamide and 2-chloro-6-fluoro benzoyl chloride (Compound No. 28).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([N:46]2[CH:50]=[N:49][C:48]([CH3:51])=[N:47]2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([N:46]5[CH:50]=[N:49][C:48]([CH3:51])=[N:47]5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1cnc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)c1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4cn(C)cn4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To solution of 4-[1-phenyl-1-(1-methylimidazol-4-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.0477 g, 0.0775 mmol) in CH2Cl2 (3 mL) was added TFA (0.3 mL) and the solution was allowed to stir at rt for 30 min. The solvent was then removed in vacuo and the material was dissolved in CHCl3. To this solution was added 4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0258 g, 0.0764 mmol) and iPrNEt2 (0.024 mL, 1.38 mmol), followed by BOP-Cl (0.0271 g, 0.106 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo and the residue was partitioned with H2O-EtOAc. The aqueous phase was re-extracted with EtOAc (×2) and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated. The resulting residue was purified by preparative HPLC (NH4OAc) to give the title compound (0.0210 g, 50%) as a colorless solid:
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:22])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:7]=2[CH:6]=[C:5]([O:23][CH3:24])[CH:4]=1.[S-]CC.[Na+].O>CN(C)C=O>[OH:2][C:3]1[C:8]2[C:9](=[O:22])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:7]=2[CH:6]=[C:5]([O:23][CH3:24])[CH:4]=1
Reactant: COc1cc(OC)c2c(c1)OCCCCC=CCCCCOC2=O
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(O)c2c(c1)OCCCCC=CCCCCOC2=O
Yield: 38 %

Procedure:
A solution of 1,3-dimethoxy-6,7,8,9,12,13,14,15-octahydro-5,16-dioxa-benzocyclopentadecen-17-one (321 mg, 0.96 mmol) and sodium thioethoxide (97 mg, 1.15 mmol) in dimethyl formamide was heated at 140° C. for 4 h whereby it was poured into water (100 ml). Extraction and chromatography gave 1-hydroxy-3-methoxy-6,7,8,9,12,13,14,15-octahydro-5,16-dioxa-benzocyclopentadecen-17-one (117 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:12][CH3:13])[CH2:9][CH3:10])=[CH:4][CH:3]=1.OC1C=CC(C(C2C=CC(O)=CC=2)(CC)CC)=CC=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.OC1C=CC(C2(C3C=CC(O)=CC=3)C=CC=CC2C=C)=CC=1.C(C1C=C(O)C=CC=1CCC1C=CC(O)=CC=1CC)C.C(C1C(O)=CC=CC=1CCC1C=CC=C(O)C=1CC)C.C/C=C(\C1C=CC(O)=CC=1)/C(/C1C=CC(O)=CC=1)=C/C.OC1C=CC(C(CC(C2C=CC(O)=CC=2)CC)CC)=CC=1.OC1C=CC(CCCCC2C=CC(O)=CC=2)=CC=1.OC1C=CC(CCCC2C=CC(O)=CC=2)=CC=1.FC1C=C(C(C2C=CC(O)=C(F)C=2)(C)C)C=CC=1O>>[CH3:13][CH2:12][C@@H:11]([C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:9][CH3:10])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1
Reactant: CCC(c1ccc(O)cc1)C(CC)c1ccc(O)cc1
Agent: C/C=C(C(=C/C)/c1ccc(O)cc1)\c1ccc(O)cc1
Agent: C=CC1C=CC=CC1(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CC(C)(c1ccc(O)c(F)c1)c1ccc(O)c(F)c1
Product: CC[C@H](c1ccc(O)cc1)[C@@H](CC)c1ccc(O)cc1

Procedure:
3,4-bis(4-hydroxyphenyl) hexane; 3,3bis(4-hydroxyphenyl)pentane; 2,2-bis(4-hydroxyphenyl) propane; 2,2-bis(4-hydroxyphenyl) styrene; 1,2-bis(2-ethyl-4-hydroxyphenyl)ethane, 1,2-bis(2-ethyl-3-hydroxyphenyl) ethane; dienestrol (3,4-bis(4-hydroyphenyl)-2,4-hexadiane); 3,5-bis(4-hydroxyphenyl) heptane; 1,4-bis(4-hydroxyphenyl)-butane, 1,3-bis(4-hydroxyphenyl) propane, 2,2-bis (3-fluoro-4-hydroxyphenyl) propane, 2,2-bis(4-hydroxyphenyl)-3'-methyl styrene, 2,2-bis(4-hydroxyphenyl)-4'-fluorostyrene and 2,2bis(4-hydroxyphenyl)-4'-trifluoromethyl styrene.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[CH2:29]([N:26]1[CH2:25][CH2:24][CH:23]([O:22][C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:6]([C:5]3[S:1][C:2]4[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=4[CH:4]=3)=[O:8])=[CH:21][C:18]=2[C:19]#[N:20])[CH2:28][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1cc(N)ccc1OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc2ccccc2s1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1OC1CCN(Cc2ccccc2)CC1
Yield: 32.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (0.7 g) and 5-amino-2-(1-benzylpiperidine-4-yloxy)benzonitrile (1.2 g), the title compound (0.6 g) was obtained. melting point: 206° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7](=[O:27])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[C:22](Cl)[N:21]=[N:20][C:19]=2[Cl:25])=[O:17])[N:13]=1.C(O)(=[O:33])C>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7](=[O:27])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[C:22]([OH:33])[N:21]=[N:20][C:19]=2[Cl:25])=[O:17])[N:13]=1
Reactant: CN(Cc1csc(NC(=O)NCc2cccc(F)c2)n1)C(=O)c1cc(Cl)nnc1Cl
Reactant: CC(=O)O
Product: CN(Cc1csc(NC(=O)NCc2cccc(F)c2)n1)C(=O)c1cc(O)nnc1Cl

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide (150 mg) in acetic acid (10 mL) was heated at reflux for 2 h. The resultant mixture was concentrated and purified by a preparative C-18 reverse phase HPLC. About 15 mg of the desired product-3-chloro-6-hydroxypyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide was obtained. The desired product was confirmed by 1HNMR and LC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[C:21]3[CH2:20][C:19]([O:22]CC)=[CH:18][CH2:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[C:21]3[CH2:20][C:19](=[O:22])[CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CCOC1=CCc2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCc2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2C1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (0.16 g, 0.84mmol) in tetrahydrofuran (15 mL) was added 4-chloro-3-trifluoromethyl-phenylisocyanate (0.22 g, 1.0 mmol). The mixture was stirred at room temperature for 1.5 hours and was poured into water. The product was extracted with ethylacetate, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen-1-yl)urea (0.31 g, 89% yield). Next, to a solution of N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen 1-yl)-urea (0.21 g, 0.51 mmol) in tetrahydrofuran (20 mL) was added a solution of aqueous 1N hydrochloric acid (5 mL), and the mixture was stirred at 40° C. for 45 minutes. The mixture was neutralized with addition of 10% aqueous sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N(4-chloro-3-tri-fluoromethyl-phenyl)-N′-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.16 g, 85% yield). Next, to N-(4-chloro-3-trifluoromethyl-phenyl)-N′-7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.07 g, 0.18 mmol) in methanol (10 mL) was added sodium borohydride (0.04 g, 0.09 mmol) at 0° C., and the mixture was stirred for 30 minutes. The mixture was poured into water, and the product was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the obtained product was recrystalized from a mixture of ethylacetate/hexane (1/2) solution to give N-[4chloro-3-(trifluoromethyl)phenyl]-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea (41 mg, 59% yield)
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11]([OH:13])=[O:12].[OH-].[Na+].[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.Cl>O1CCOCC1.O>[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][C@@H:3]2[C:11]([OH:13])=[O:12])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@H]1Cc2ccccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)N2c3ccccc3C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of the title C compound, (R)-2,3-dihydro-1H-indole-2-carboxylic acid hydrochloride (0.92 g, 4.6 mmol), 1N aqueous sodium hydroxide (12.0 mL, 12 mmol) and water (25 mL) at room temperature is added dropwise a solution of 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride (1.65 g, 4.6 mmol) in dioxane (33 mL). Upon completion of the addition, the pH of the reaction mixture is monitored and maintained between 7–8 by slow addition of 1N aqueous sodium hydroxide over the next 2 hours. The reaction mixture is stirred overnight at room temperature. The solution is poured into crushed ice and the resulting mixture is acidified to pH 2–3 with 1N aqueous hydrochloric acid (11 mL). The precipitate that forms is collected, washed with water and dried under high vacuum overnight to give 1.5 g of (R)-1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid: [M+1]+=491.2, [M−1]−=489.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[C:10]([CH3:27])([CH3:26])[N:9]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]3[C:22]([CH3:25])=[N:23][N:24]=[C:11]3[C:10]([CH3:27])([CH3:26])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1F)=NC2(C)C
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: Cc1nnc2n1-c1ccc(N)cc1C(c1ccccc1F)=NC2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
43.6 g (0.12 mol) of 6-(o-fluorophenyl)-1,4,4-trimethyl-8-nitro-4H-s-triazolo[4,3-a][1,4]benzodiazepine in 600 ml of concentrated hydrochloric acid are treated portionwise with a total of 80.55 g (0.36 mol) of tin chloride in such a manner that the temperature of the mixture does not exceed 85° C. Subsequently, the mixture is stirred at room temperature for 1 hour, cooled to 0° C. and cautiously neutralised with 900 ml of 10 N sodium hydroxide. After extracting the remaining suspension three times with methylene chloride, the combined organic phases are washed with saturated sodium chloride solution, dried and evaporated. Recrystallisation of the residue from 350 ml of ethanol at -30° C. gives 8-amino-6-(o-fluorophenyl)-1,4,4-trimethyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 294° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)([O-:3])=[O:2].Cl[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=1)[CH:29]=[O:30].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].COCCOC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][C:5]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=1)[CH:29]=[O:30])([O-:3])=[O:2]
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2[N+](=O)[O-])OC1(C)C
Reactant: O=Cc1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=Cc1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1

Procedure:
A mixture of 200 mg of 1-(4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine 1e, 85 mg of 2-chloroisonicotinaldehyde, 6.7 mg of Pd(OAc)2, 31 mg of PPh3, 1.25 mL of 2 N aqueous Na2CO3 solution, and 3 mL of DME were refluxed 2 h. The mixture was diluted with ethyl acetate and washed 3× with water. The organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel eluting with 10% ethyl acetate in dichloromethane. This gave 114 mg of product. MS (ES, m/z): 312.0 [M+H]+.
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13](C=O)=[CH:12][CH:11]=1>ClCCl>[CH3:3][O:2][CH:1]([O:4][CH3:5])[C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1
Reactant: COC(OC)OC
Reactant: CSc1ccc(C=O)cc1
Solvent: ClCCl
Product: COC(OC)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.9 %

Procedure:
A suspension of K-10 (32 g) in trimethyl orthoformate (115 ml, 1.05 mol) was added to a solution of 4-(methylthio)benzaldehyde (31.0 g, 0.203 mol) in dichloromethane (300 ml) at 0° C. The obtained mixture was stirred at room temperature for 20 minutes and filtered to remove the K-10. The filter cake was washed with dichloromethane. The filtrate and washings were together washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum to give the title compound as a pale-yellow oil (39.0 g, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1>O1CCOCC1>[N:16]1([C:14]2[C:9]3[NH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:20]=[CH:19][CH:18]=[N:17]1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c2c(-n3cccn3)ncnc12
Temperature: 25 °C
Yield: 14.6 %

Procedure:
In a sealed tube 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carbonyl chloride 5 (2.0 g, 8.9 mmol), pyrazole (1.8 g, 26.5 mmol) and 1,4 dioxane (10 mL) were heated at 138° C. for 2 h. Upon cooling to ambient temperature a precipitate formed which was collected and washed with saturated aqueous NaHCO3 and diethyl ether to yield 49 (340 mg, 1,3 mmol) as a white solid. The filtrate was treated with saturated aqueous NaHCO3 (20 ml) and the resulting precipitate was washed with saturated aqueous NaHCO3 and diethyl ether to yield additional 49 (2.0 g, 7.8 mmol, 99% total yield). 1H NMR: (500 MHz, CD3OD) δ 8.99 (br s, 1H), 8.78 (br s, 1H), 8.29 (s, 1H), 8.06 (br s, 1H), 6.72 (br s, 1H), 4.30 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H); LC/MS: (ES+) m/z (M+H)+=258; HPLC Rt=1.20 min., column L.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([N:15]([CH3:16])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]3)=[CH:14][CH:13]=2)=[O:32])=[CH:27][CH:26]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
1,1-Dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazine-carboxylate (D3) (0.4 g, 1.254 mmol) was taken up in DCM (4 mL) under argon. 6-Chloro-3-pyridinecarbonyl chloride (0.243 g, 1.379 mmol) in DCM (4 mL) and triethylamine (0.348 mL, 2.508 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM (×2) and the combined organics dried and concentrated to a pale yellow oil. The crude product was purified by column chromatography. Elution with a 0-50% EtOAc/petroleum ether gradient yielded the title compound as a white foam/gum (0.601 g). δH (CDCl3, 400 MHz) 8.21 (1H, d), 7.61 (1H, dd), 7.25 (2H, d), 7.16 (1H, d), 6.99 (2H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.50 (3H, s), 3.47 (1H, d), 3.34 (1H, d), 3.10 (1H, td), 2.70 (1H, d), 2.49 (1H, d), 2.10 (1H, dd), 2.00 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 459.2.