Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[C:12]#[N:13])=[C:4]([N+:22]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:26]>C(O)C.Cl>[ClH:26].[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[N:22]=[C:12]([NH2:13])[C:11]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:10]=3[NH:9][C:5]=2[CH:6]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(F)c(F)cc2Nc2ccc(C(F)(F)F)cc21
Yield: 63.8 %

Procedure:
Heat a solution of 2-(4,5-difluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (0.995 g, 2.90 mmol) in ethanol (15 ml) to 60° C. Add to this a solution of tin (II) chloride (1.65 g, 8.70 mmol) in 5.0 N hydrochloric acid (15 ml). Heat the resulting mixture to reflux for 18 hours. Cool the reaction to room temperature, add 30 ml of 5.0 N hydrochloric acid and place the mixture in a freezer for 16 hours. Collect by filtration the precipitated product from the solution. Wash solid with 5.0 N hydrochloric acid to obtain 0.648 g of the title compound (1.85 mmol, 64% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 314(M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=O)=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCOC(CN)OCC
Product: CCOC(CNCc1ccnc2ccccc12)OCC
Reaction time: 8 h
Yield: 109.3 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (3.64 ml, 25 mmol) was reacted with 4-quinolinecarboxaldehyde (3.14 g, 20 mmol) to obtain the title compound (6.0 g, 88%).
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O-:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:26][CH2:27][C:28]#[N:29]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:29][CH2:28][C:27]#[N:26])=[O:14])=[CH:7][CH:8]=1
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1ccccn1)C(=O)[O-]
Reactant: N#CCN
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1ccccn1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 17, step 3, 2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-4-methylpentanoic acid potassium salt from step 3 (662 mg, 1.59 mmol) was coupled with aminoacetonitrile HCl Salt. The crude residue obtained was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].CCN(C(C)C)C(C)C.Br[C:23]1[N:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=1>C(O)CCC>[Br:29][C:26]1[CH:25]=[N:24][C:23]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][CH:10]([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[N:28][CH:27]=1
Reactant: Brc1cnc(Br)nc1
Reactant: Nc1ccc(OC(F)F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: FC(F)Oc1ccc(Nc2ncc(Br)cn2)cc1Cl
Temperature: 120 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
To a solution of 3-chloro-4-(difluoromethoxy)aniline (0.814 g, 4.20 mmol) in butan-1-ol (10 mL), were added DIPEA (2.203 mL, 12.61 mmol) and 2,5-dibromopyrimidine (1 g, 4.20 mmol). The reaction mixture was stirred at 120° C. for 12 h and concentrated. The crude product was purified by flash chromatography on silica gel using 3% ethyl acetate in petroleum ether to give 5-bromo-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.8 g, 64%). LCMS (ES-ES), m/z 349.98.
Reaction SMILES: [C:1]1([CH:7]([O:9][C:10]([C:12]2([C:35]([O:37]C(C3C=CC=CC=3)C)=[O:36])[O:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][C@H:22]([NH:24][CH2:25][C@@H:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[OH:27])[CH3:23])=[CH:20][C:14]=3[O:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.CO>[C:1]1([CH:7]([O:9][C:10]([C:12]2([C:35]([OH:37])=[O:36])[O:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][C@H:22]([NH:24][CH2:25][C@@H:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[OH:27])[CH3:23])=[CH:20][C:14]=3[O:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(OC(=O)C1(C(=O)OC(C)c2ccccc2)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(OC(=O)C1(C(=O)O)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1)c1ccccc1
Yield: 22 %

Procedure:
The title compound was prepared as a tan solid according to the procedure of Example 102 from 5-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-phenylethyl) ester; yield: 22%; Rf =0.39 (9/1 CHCl3 /MeOH; mp 71-79° C.; 1H NMR (300 MHz, DMSO-d6): δ 1.00 (d, 3H), δ 1.5 (br m, 3H), δ 2.4-2.75 (m, 1H), δ 3.15-3.45(br m, 5H), δ 4.90 (br d, 1H), δ 5.20 (br d, 1H), δ 5.90 (q, 1H), δ 6.6 (d, 1H), δ 6.76 (d, 2H), δ 7.21 (br s, 6H), δ 7.36 (m, 3H), δ 7.46 (s, 1H); MS (ES) m/z (relative intensity): 526 (M+, 100).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:25][CH2:24][C@H:23]([NH:26]C(=O)OCC5C=CC=CC=5)[C@H:22]([F:37])[CH2:21]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>O.C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH:22]([F:37])[CH2:21]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(N[C@H]1CCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1F)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: NC1CCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)CC1F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To the product from Step G (0.185 g, 0.373 mmol) was added HCl (1.86 mL, 11.2 mmol, 6.0M aqueous) and the solution was warmed to 90° C. and stirred for 0.5 hours. The mixture was cooled to ambient temperature and diluted with water (10 mL) and with CH2Cl2 (10 mL). The layers were mixed and separated and the aqueous phase was treated with saturated aqueous Na2CO3 until pH=10. The aqueous phase was extracted with CH2Cl2 (4×10 mL). The combined organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography (1 to 10% MeOH w/6% NH4OH/CH2Cl2) to afford 0.094 g (69%) of the desired product as a pale yellow/orange solid. MS ESI (+) m/z 363.2 (M+1) detected.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH:24]1[O:26][CH2:25]1>CO>[CH2:1]([N:8]([CH2:25][CH:24]([OH:26])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[Cl:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1C1CO1
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Solvent: CO
Product: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccccc2Cl)cc1OC

Procedure:
Similarly 2.71 g. (0.01 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 2.33 g. (0.015 mol) of o-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-chlorophenyl)ethylamine. The latter is converted to its hydrochloride, which is dissolved in 90 ml. of methanol and hydrogenated over 1 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature for six hours. The reaction mixture is filtered and evaporated in vacuo to leave N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-chlorophenyl)ethylamine hydrochloride, m.p. 128°-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:25]([CH:22]4[CH2:24][CH2:23]4)=[O:26])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)C1CC1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)C2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)cyclopropanecarboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and cyclopropanecarboxylic acid using method D. NMR; δH [2H6]—DMSO 10.18,(1H, s), 8.60,(1H, t), 7.91,(2H, d), 7.50-7.47,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.16,(2H, t), 2.16,(3H, s), 1.74,(1H, m),1.04,(1H, m), 0.77-0.75,(4H, m), 0.43,(2H, m), 0.23,(2H, m). LCMS: retention time 3.19 min, MH+349.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:26][C@H:27]1[O:29][CH2:28]1)(=O)=O.O>CN(C=O)C>[CH2:26]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2)[C@H:27]1[O:29][CH2:28]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(OC[C@@H]3CO3)cccc2[nH]1
Reaction time: 24 h
Yield: 178.6 %

Procedure:
To a solution of ethyl 4-hydroxy-1H-indole-2-carboxylate (1.3 g) in DMF (50 ml) were added potassium carbonate and (S)-glycidyl nosylate (1.0 g) and the mixture was stirred one day. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give ethyl (S)-4-glycidyloxy-1H-indole-2-carboxylate (1.8 g) as a brown oil. This was dissolved in methanol (50 ml) and the solution was refluxed under heating with 4-(naphthalen-2-yl)piperidine (1.5 g) for 3 hr. The solvent was evaporated under reduced pressure to give ethyl (S)-4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-1H-indole-2-carboxylate (1.4 g) as pale-brown crystals (melting point 115–117° C.). By the reactions in the same manner as in Starting Material Synthesis Example 22, the title compound (1.1 g) was obtained as white crystals, melting point 171–173° C.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)C1)=O)(C)(C)C.[C:33]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][CH2:47][CH:41]1CNC2)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][CH2:47][CH:41]1[CH2:11][N:12]([CH2:16][C:17]1[S:25][C:24]3[C:23]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[N:22][C:21]([Cl:32])=[N:20][C:19]=3[CH:18]=1)[CH2:13]2)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a tan solid (103 mg, 74%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C([Li])(C)(C)C.[CH:16](=[O:18])[CH3:17]>C1COCC1.CCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:16]([OH:18])[CH3:17]
Reactant: COCOc1cccnc1
Reactant: CC=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCOc1cnccc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A solution of 3-(methoxymethoxy)pyridine (9.8 g, 70 mmol) and THF (40 mL) was added to a stirring mixture of tert-butyllithium (91 mL of a 1.7 M solution with pentane, 160 mmol) and THF (100 mL) at −780° C. After 1 h, acetaldehyde (9.9 mL, 180 mmol) was added, and the reaction mixture was stirred for 3 h and then warmed to RT. After 21 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, the layers were separated, the organic material was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (1:1 hexane-ethyl acetate) to afford 4.6 g (36%) of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanol as a colorless solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH:9]1[C:17](=O)[C:15](=O)[C:13](=[O:14])[NH:12][C:10]1=[O:11]>O>[CH:4]1[CH:5]=[CH:6][C:1]2[C:2](=[N:7][C:15]3[C:13](=[O:14])[NH:12][C:10](=[O:11])[NH:9][C:17]=3[N:8]=2)[CH:3]=1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Nc1ccccc1N
Solvent: O
Product: O=c1[nH]c(=O)c2nc3ccccc3nc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
There was charged 800 ml of water into an Erlenmeyer flask, then 3.5 g (30 mmoles) of o-phenylenediamine and 5.0 g (30 mmoles) of alloxan were added thereto, and the mixture was stirred at room temperature in a nitrogen atmosphere for about 5 hours. The obtained reaction mixture was cooled with ice for 3 hours, then the formed yellow precipitate was filtered off, and washed in ethanol and ether (50 ml, twice). This precipitate was recrystallized from an aqueous dimethylformamide solution to give pale yellow powdery crystals. Yield: 7.5 g (90%). M.p. 300° C. or higher. IR spectrum: Found values (cm-1): 1730, 1705 (C=O stretching), 1572 (Broad peak) --C=N (amide II band). Literature values (cm-1): 1727, 1700, 1574.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[C:13]1([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(=S)=S>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([C:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: COc1ccc(C(=O)Cl)cc1C
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Temperature: 25 °C

Procedure:
To a cooled, stirred solution of 10.8 g. (0.058 mol.) of 3-methyl-4-methoxybenzoic acid chloride and 9.6 g. (0.054 mol.) of 2-phenylbenzofuran in 40 ml. of carbon disulfide is added dropwise over a 20 minute interval 28.2 g. (0.108 mol.) of stannic chloride. After addition, the reaction mixture is warmed to ambient temperature and stirred for 2 hours. The mixture is then poured onto 100 ml. of ice-water and stirred for 1 hour. The solvent is removed, and the product extracted into chloroform and the extracts are washed with water, dried (Na2SO4) and concentrated under reduced pressure to give 3-(3-methyl-4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:19]([C:18]1[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[C:24]([O:25][CH3:26])[C:17]=1[O:16][CH3:15])[OH:20])[CH3:5])[CH3:2]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: C#CCOC(C)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(OC)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
A solution of 8 g (62.4 mmol) of 1-(1-ethoxyethoxy)-2propyne in 135 ml of tetrahydrofuran was treated at -78° under argon with 39 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 12.3 g (62.4 mmol) of 2,3,4-trimethoxybenzaldehyde in 53 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0°, stirred at 0° for a further 1 hour and then treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 600 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1-(2,3,4-trimethoxyphenyl)-2 -butyn- 1-ol as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12].ClCCl.ClC1C=CC=C(C(OO)=[O:36])C=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:36])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75.9 mg (0.20 mmol) of the compound from Example 7 were introduced into 11 ml of dichloromethane at 0° C., 49.2 mg (0.20 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 50 mg (63% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:12][N:13]=[N+]=[N-])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[N+:17]([C:20]1[CH:30]=[CH:29][C:23]([CH2:24][O:25][C:26](Cl)=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)CC)C>CO.[Pd]>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25][C:26](=[O:27])[NH:13][CH2:12][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH:9]([CH3:11])[CH3:10])=[CH:29][CH:30]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of ((1S)-1-azidomethyl-2methylpropyl)-carbamic acid t-butyl ester (3.26 g, 13.3 mmol) (obtained as described in Reference Example 61(2)) in methanol (160 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (3.26 g) at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (160 ml) were added chloroformic acid p-nitrobenzyl ester (4.31 g, 20.0 mmol) and triethylamine (2.80 ml, 20.0 mmol) in an ice bath, and then the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (8:1→1:1) as the eluant to afford ((2S)-2-t-butoxycarbonylamino-3-methylbutyl)carbamic acid p-nitrobenzyl ester (3.13 mg, yield 62%) as pale yellow crystals.
Reaction SMILES: [CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16](=[O:22])OC(C)(C)C)[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:4])=[O:3].N1C=CC=CC=1.ClC([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>Cl.O1CCOCC1>[CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[O:22])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2CS(C)(=O)=O)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(ccn3CS(C)(=O)=O)cn2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
A mixture of tert-butyl 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (8D, 420 mg, 1.3 mmol) in 4M HCl in dioxane (3 ml) was stirred at 50° C. for 3 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in pyridine (3 ml, 37.1 mmol). To the mixture, methyl 4-(chlorocarbonyl)benzoate (385 mg, 1.936 mmol) was added and stirred at room temperature for 3 h. The mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (NH—SiO2, EtOAc) to give methyl 4-(1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (8E, 160 mg, 0.40 mmol, 31% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (s, 3H) 3.90 (s, 3H) 5.88 (s, 2H) 6.73 (d, J=2.78 Hz, 1H) 7.49 (d, J=3.28 Hz, 1H) 8.01-8.12 (m, 2H) 8.12-8.19 (m, 2H) 8.46 (s, 1H) 8.70 (s, 1H) 10.93 (s, 1H).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17]3)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:24]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36]([CH:41]=O)=[CH:35]3)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[C:17]3=[CH:41][C:36]2[NH:37][C:38]3[C:34]([CH:35]=2)=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:40][CH:39]=3)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
5-(3,4-Dihydro-2H-quinoline-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>O1CCCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Yield: 49.1 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (0.200 g, 0.624 mmol) and 1-fluoro-4-isocyanatobenzene (0.257 g, 1.87 mmol) in a 25 mL round-bottomed flask was added tetrahydrofuran (10 mL). The solution was heated to 65° C. for 2 hours before the solvent was removed under reduced pressure. Purification by flash column chromatography provided the title compound (0.140 g, 49%).