Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCc1ccccc1

Procedure:
102 g of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 85.6 g of benzylamine are boiled under reflux for 2 hours. Water and excess benzylamine are then distilled off (39 ml at 105° C. under 4,132 Pa).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](=[O:25])[C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[CH:12]=[CH:11][N:10]=1>N1C=CC=CC=1>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[C:16]([NH:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:2](=[O:3])[O:4][CH:5]([CH3:7])[CH3:6])[CH:14]=1)=[O:25]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
To a stirred solution of isopropyl chloroformate (0.066 g, 0.53 mmol) in 3 ml of pyridine was added N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (0.1 g, 0.36 mmol). The resulting mixture was stirred for another 30 min and then concentrated under reduced pressure. The residue was purified via prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a white solid (0.025 g, yield: 19%). 1H NMR (DMSO-d6, 500 MHz): δ 11.17 (s, 1H), 9.97 (s, 1H), 8.21-8.17 (m, 2H), 7.61-7.53 (m, 3H), 7.40 (m, 1H), 4.90 (m, 1H), 1.25 (t, J=5.5 Hz, 6H). LCMS (ESI) m/z: 368.0 [M+H+].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:12]=[CH:13][N:14]([CH3:17])[C:15]=2Br)[CH:6]=1)=[O:4].[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2B(O)O)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[C:15]2[N:14]([CH3:17])[CH:13]=[N:12][C:11]=2[C:7]2[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][N:8]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccnc(-c2ncn(C)c2Br)c1
Reactant: OB(O)c1ccc(F)cc1OCC1CC1
Product: Cn1cnc(-c2cc(C(=O)O)ccn2)c1-c1ccc(F)cc1OCC1CC1
Yield: 10 %

Procedure:
The title compound was prepared in 10% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carboxylic acid methyl ester and 2-(cyclopropylmethoxy)-4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A followed by hydrolysis. 1H NMR (400 MHz, DMSO-d6): δ 0.10 (2H, m), 0.32-0.39 (2H, m), 0.88-0.93 (1H, m), 3.44 (3H, s), 3.69 (1H, m), 3.81 (1H, m), 6.80 (1H, td, J=2.4 and 8.4 Hz), 6.96 (1H, dd, J=2.4 and 11.6 Hz), 7.27 (1H, t, J=7.7 Hz), 7.45 (1H, dd, J=1.5 and 5.1 Hz), 7.84 (1H, s), 8.28 (1H, s), 8.31 (1H, d, J=5.0 Hz). [M+H] Calc'd for C20H18FN3O3, 368. Found, 368.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:25]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3-[2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid(12.3 g) was dissolved in 150 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. 4-(2-Aminoethyl)morpholine (7.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 12.5 g (80%) of 3-[2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-N-(2-morpholin-4-ylethyl)-propionamide.
Reaction SMILES: [S:1](=[O:30])(=[O:29])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[NH:23][CH2:24]CCC)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].[Si](I)(C)(C)[CH3:32]>>[S:1](=[O:29])(=[O:30])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[N:23]([CH3:32])[CH3:24])=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: C[Si](C)(C)I
Reactant: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Product: CN(C)C(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C

Procedure:
Compound 11p was synthesized in a similar manner as 11a except that TMS-I was used in place of BBr3. Compound 11p was prepared from compound 12. EI-MS m/z 404 M+; 1H NMR (300 MHz, DMSO-d6) δ 0.98 (s, 3H, CH3), 2.93 (brs, 6H, N(CH3)2), 5.86 (s, 1H, 16-CH), 6.97 (s, 1H, ArH), 7.02 (d, 1H, J=9 Hz, ArH), 7.31 (d, 1H, J=9 Hz, ArH), 7.89 (s, 2H, SO2NH2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH2:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH:20][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1
Reactant: Cc1cccc(-c2sc(N)nc2-c2cc(C)nc(C)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2sc(NC(=O)Nc3ccccc3)nc2-c2cc(C)nc(C)c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 48.2 %

Procedure:
To a solution of [4-(2,6-dimethyl-4-pyridyl)-5-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.7 mmol) in N,N-dimethylacetamide (20 mL) was added phenyl isocyanate (0.28 mL, 2.6 mmol), and the mixture was stirred for 14 hours at 80° C. Aqueous sodium hydrogen carbonate was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with brine, then, dried to be concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1). The resulted crude crystal was recrystallized from ethyl acetate-hexane to obtain a title compound (0.34 g, yield 48%).
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10]([Cl:14])=[CH:11][C:12](Cl)=[C:7]2[C:6]([CH3:15])=[CH:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1.C(OCC)(=O)C>CS(C)=O>[Cl:14][C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([CH3:15])[C:7]2=[C:12]([O:29][C:26]2[CH:27]=[CH:28][C:23]([NH2:22])=[CH:24][C:25]=2[F:30])[CH:11]=1
Reactant: CC(=O)n1cc(C)c2c(Cl)cc(Cl)nc21
Reactant: Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c[nH]c2nc(Cl)cc(Oc3ccc(N)cc3F)c12
Temperature: 120 °C

Procedure:
300 mg (1.16 mmol) of 1-acetyl-4,6-dichloro-3-methyl-1H-pyrrolo[2,3-b]pyridine (from example XL) and 320 mg (2.32 mmol) of powdered potassium carbonate are suspended in 9 ml of DMSO. The mixture is degassed, and 442 mg (3.48 mmol) of 4-amino-2-fluorophenol are added. The mixture is heated at 120° C. for 4 hours. After addition of ethyl acetate, the mixture is filtered off with suction through CELITE (diatomaceous earth) and the filtercake is washed with ethyl acetate. The filtrate is extracted three times with sat. sodium bicarbonate solution and with sat. sodium chloride solution. The filtrate is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel 60, mobile phase: DCM:methanol=50:1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:18]([O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1cc(CO)on1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.4 %

Procedure:
14.22 g of ethyl 5-(hydroxymethyl)-isoxazole-3-carboxylate was dissolved in 80 ml of N,N-dimethylformamide, and 6.13 g of imidazole and 13.57 g of t-butyldimethylsilyl chloride were then added. The mixture was stirred at room temperature for 10 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain 23.82 g of ethyl 5-(t-butyldimethylsilanyloxymethyl)-isoxazole-3-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC([N:33]1[CH2:38][CH2:37][N:36]([S:39]([C:42]2[S:43][C:44](Br)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:36]1([S:39]([C:42]2[S:43][C:44]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)=[N:8][C:7]=34)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34][NH:33][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1)N1CCNCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 4-(5-bromo-thiophene-2-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (example B.52) (206 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (96 mg, 33%). MS (ISP) 586.1 [(M+H)+]; mp 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:23]([O:25][C:26](=[O:34])[CH2:27][C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:34])[CH2:27][C:28]1[N:29]=[C:30]([NH:33][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])[S:31][CH:32]=1)[CH3:24]
Reactant: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CC2
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)n1

Procedure:
The title compound was prepared as for example 8, steps 1 to 4. Step 1 was performed using 3-chlorobenzensulfonyl chloride and yielded 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester) which was hydrolyzed to 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid in step 2 and coupled to (2-amino-thiazol-4-yl)-acetic acid ethyl ester in step 3 to yield (2-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester. This was hydrolyzed to (2-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid in step 4: white solid, 0.08 g (96%), MS (ISP): m/e=476.0 (M−H).
Reaction SMILES: [Br-].[CH2:2]([C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:33]([CH:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)#[N:34].O>COC(C)(C)C>[CH2:2]([C:7]1[CH:32]=[CH:31][C:10]([CH:11]=[CH:41][CH:38]2[CH2:39][CH2:40][CH:35]([C:33]#[N:34])[CH2:36][CH2:37]2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N#CC1CCC(C=O)CC1
Reactant: CCCCCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCCc1ccc(C=CC2CCC(C#N)CC2)cc1
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A mixture of 2.51 g of p-pentylbenzyl-triphenylphosphonium bromide and 615 mg of a cis/trans mixture (about 1:1) of 4-cyanocyclohexanecarboxaldehyde in 30 ml of t-butyl methyl ether was placed at 0° C. under argon gasification in a sulphonation flask fitted with a thermometer and solid substance addition tube, treated within 2 minutes with 673 mg of solid potassium t-butylate and subsequently stirred for a further 1.5 hours. The red-brown heterogeneous mixture was then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was suspended in 150 ml of hexane, freed from precipitated triphenylphosphine oxide by filtration (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.4 bar) of the resulting oil (1.36 g) on silica gel using 3% ethyl acetate/petroleum ether as the eluting agent gave 1.02 g (81%) of 4-[2-(p-pentylphenyl)ethenyl]cyclohexanecarbonitrile as a colourless oil; Rf values (10% ethyl acetate/petroleum ether): 0.27 and 0.37 (stereoisomer mixture).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:11][C:10]1[C:9]2[C:12]([CH2:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1oc2cccc(CC)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.8 %

Procedure:
To a solution of 0.380 g (1.64 mmol) of 3-methyl-4-ethylbenzofuran-2-carboxylicacid ethyl ester in 8 mL of methanol and 8 mL of THF was added 8.2 mL of 1N sodium hydroxide solution and the reaction was stirred for 14 h at room temperature and then acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 0.321 g of 3-methyl-4-ethylbenzofuran-2-carboxylic acid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25]O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[I:27]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][I:27])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: II
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Under a nitrogen atmosphere, a solution of diethyl azodicarboxylate (4.699 g, 26.98 mmol) in dry tetrahydrofuran (THF) (15 mL) was added drop-wise to an ice-cold stirring solution of (2S)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine (5.37 g, 26.7 mmol), iodine (3.42 g, 13.5 mmol) and triphenylphosphine (7.069 g, 26.95 mmol) in dry THF (50 mL). The mixture was stirred and allowed to warm to ambient temperature overnight. The mixture was concentrated on a rotary evaporator and then the residue was stirred with 5% aqueous Na2S2O3 (50 mL). After stirring for 30 min, the mixture was extracted with dichloromethane (4×25 mL). The combined dichloromethane extracts were dried (Na2SO4), filtered and concentrated. The residue was repeatedly crystallized (three to four times) from dry ether and finally from heptane to give 3.20 g (38.6%) of product.
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:51])=[C:32]([CH:38]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:51][C:31]1[C:32]([CH:38]2[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]2)=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=1[NH:29][C:7]1[N:6]=[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)[C:10]2=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]2[N:8]=1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C#N)cc(N)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCNCC2)c1
Temperature: 70 °C

Procedure:
A mixture of 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (142 mg, 0.357 mmol), tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (100 mg, 0.298 mmol) and Cs2CO3 (194 mg, 0.596 mmol) in DMF (3 mL) was heated at 70° C. for 2 h. This was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The crude mixture containing 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was carried forward to next step.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:20][N:21]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:62])[CH2:36][CH2:37][C:38](=[O:61])[N:39]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:22](=[O:28])[CH2:23][CH2:24][C:25](O)=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.Cl.[CH2:65]([O:72][NH:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][NH2:79])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C(Cl)Cl>[C:49]([O:48][C:46]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][N:39]([O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:38](=[O:61])[CH2:37][CH2:36][C:35](=[O:62])[NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][N:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25](=[O:26])[NH:79][CH2:78][CH2:77][CH2:76][CH2:75][CH2:74][NH:73][O:72][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:47])([CH3:51])([CH3:50])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Reactant: NCCCCCNOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
CDI (0.188 g, 1.16 mmol) was added to a solution of (10) (0.76 g, 1.09 mmol) in dry CH2Cl2 (45 mL). The solution was cooled to 0° C. after 1 hour and (6) (free amine, 0.240 g, 1.15 mmol) was added by cannula in CH2Cl2 (60 mL) over 5 minutes. The reaction was stirred at 0° C. to room temperature for 24 hours. Solvent was removed in vacuo and dilute brine (100 mL) was added to the residue. Extraction was carried out with EtOAc (5×75 mL), followed by washing with 50 mL of cold 0.5M citric acid, 5% NaHCO3, water and brine. Solvent removal gave 0.87 g (90% ) of (11) which was used directly in the next reaction: NMR δ 1.1-1.8 (m+s, 27 H) , 2.3-3.7 (m, 20 H), 4.5 (br s, 1 H), 4.67 (s, 2 H), 4.82 (s, 4 H), 6.2 (br s, 1 H), 7.2-7.4 (m, 15 H). An analytical sample of (11) was obtained from silica gel column chromatography, eluting with 5% MeOH/CHCl3. Anal. calcd. for C49H72N6O9 : C, 66.19; H, 8.16; N, 9.45. Found: C, 66.18; H, 8.17; N, 9.42.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9](/[CH:14]=[CH:15]/[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:34][C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40](Cl)=[O:41].C(=O)([O-])O.[Na+]>C1COCC1>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](/[CH:15]=[CH:14]/[C:9]2[CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH:12]=[CH:11][C:10]=2[NH:13][C:40]([C:36]2[S:37][CH:38]=[CH:39][C:35]=2[CH3:34])=[O:41])=[N:17]1
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CCN(CC)CCOc1ccc(N)c(/C=C/c2n[nH]c3ccccc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc(NC(=O)c2sccc2C)c(/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
Crude (E)-N-(2-{3-[2-(1H-indazol-3-yl)vinyl]-4-nitrophenyloxy}ethyl)diethylamine (2.0 g, 5.2 mmol) obtained in Step 1 was dissolved in ethanol (20 mL) and the solution was treated by tin (1.9 g, 16 mmol) and concentrated hydrochloric acid (1.0 mL) at room temperature in a similar manner to Example 2, to obtain (E)-{4-[2-(diethylamino)ethoxy]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}amine. In a similar manner to Example 29, (E)-{4-[2-(diethylamino)ethoxy]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}amine (0.49 g, 1.4 mmol) was dissolved in THF (15 mL) and the solution was added with triethylamine (0.58 ml, 4.2 mmol) and 3-methylthiophenecarbonyl chloride (0.23 g, 1.4 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was triturated in ethyl acetate to obtain Compound 237 (0.42 g, 63%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[C:11]([O:4][CH2:3][CH2:2][Br:1])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromoethanol (0.36 mL) and pyridine (0.61 mL) in tetrahydrofuran (5 mL) was added pivaloyl chloride (0.62 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (2-bromoethyl) pivalate (1.04 g). A mixture of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.93 g), (2-bromoethyl)pivalate (0.82 g), cesium carbonate (1.27 g) and sodium iodide (0.2 g) in N,N-dimethylformamide (10 mL) was stirred at 65° C. for 6 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/1) to give the title compound (0.73 g).