Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH:5]2[OH:12].I[CH3:14]>ClCCl>[CH3:14][O:6][C:7](=[O:11])[C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[CH:5]=[O:12]
Reactant: CI
Reactant: O=C1OC(O)c2cc(Cl)ccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
A solution of 5-chloro-3-hydroxy-3H-isobenzofuran-1-one (10 g, 54 mmol) and iodomethane (80 g, 560 mmol) in dichloromethane (200 mL) was heated at reflux, then the heating bath was removed. To the above solution was added triethylamine (60 g) at a rate that maintained a brisk reflux. After the addition was completed, the mixture was allowed to cool to room temperature and stirred for 72 h. The mixture was purified by column chromatography to give the title product (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C=Cc1cc(OC(=O)OC)ccc1OC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cc(OC(=O)OC)ccc1OC
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of ethyl 3-(2-methoxy-5-(methoxycarbonyloxy)phenyl)acrylate (1.00 g) in methanol (3.0 mL) was added 10% palladium-activated carbon (100 mg), and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (800 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][O-:15].[Na+].[Na]>CO>[CH3:14][O:15][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[O-]
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1C(=O)O
Yield: 73 %

Procedure:
To 2-chloro-5-nitro-nicotinic acid (1.0 mmol) in methanol was added a solution of sodium methoxide in methanol (2.4 mmol, freshly prepared from sodium metal in methanol). The solution was refluxed for 2 h and the mixture was allowed to cool and concentrated in vacuo. To the resulting residue was added 10% citric acid solution (20 ml) and the solution extracted with ethyl acetate (20 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was crystallised from water to give a yellow-white solid (73%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:21]([C:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([C:9]4[CH:10]=[C:5]([C:2](=[O:4])[CH3:3])[CH:6]=[CH:7][C:8]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:12]=3[NH:19][C:18]=2[CH3:20])=[O:22])[CH2:25][CH2:26]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-N-(trans-4-aminocyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f56) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: [Pd]
Solvent: CO
Product: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Reaction time: 10 h
Yield: 95 %

Procedure:
To a solution of 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.1 g, 2.76 mmol) in MeOH (15 mL) was added Pd/C (10%, 0.110 g) and the reaction mixture was stirred under H2 (1 atm) for 10 h. The catalyst was removed by filtration, washing with methanol (3×5 mL). The filtrate was concentrated in vacuo to give 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 100%). LC/MS (Table 1, Method 3) Rt=1.428 min.; MS m/z: 401 [M+H]+.
Reaction SMILES: [CH2:1]([C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[CH2:19][CH2:18][C:17]([P:21](=[O:28])([O:25]CC)[O:22]CC)([OH:20])[CH2:16]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].I[Si](C)(C)C>C(Cl)(Cl)Cl>[CH2:1]([C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[CH2:19][CH2:18][C:17]([P:21](=[O:22])([OH:25])[OH:28])([OH:20])[CH2:16]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(CN2CCC(O)(P(=O)(OCC)OCC)C2)cc1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCc1ccc(CN2CCC(O)(P(=O)(O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
A solution of 33 mg (0.075 mmol) of (R/S)-1-(4-nonylbenzyl)-3-hydroxypyrrolidin-3-ylphosphonic acid, diethyl ester (from Step E) in 1 mL of chloroform was treated with 0.053 mL (0.37 mmol) of iodotrimethylsilane. The reaction was allowed to stir at rt for 1 h. The reaction was quenched with MeOH and concentrated several times from MeOH. The residue was purified using LC-2 to afford 4.6 mg (16%) of the title compound: ESI-MS 385 (M+H); LC-1: 3.01 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)[CH3:35])[C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCc2c([nH]c3ccc(Cl)cc23)C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(Cl)ccc31)CCN(C)C2)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.3 %

Procedure:
6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (69 mg, 0.31 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (6 mg, 0.031 mmol), L-proline (7 mg, 0.063 mmol), K3PO4 (134 mg, 0.63 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure; the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 28 mg of 6-chloro-9-(2-(3,4-dichlorophenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.95 (s, 1H), 7.62 (m, 3H), 7.30 (d, 1H), 7.20 (m, 2H), 4.30 (m, 2H), 3.40 (m, 2H), 3.0 (m, 2H), 2.82 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[O:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][O:15]1.I[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1COCC1>[F:6][C:7]1[C:12]([F:13])=[C:11]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:10]=[CH:9][C:8]=1[CH:14]1[O:15][CH2:16][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19]1
Reactant: CCCCCCCCCC1COC(c2cccc(F)c2F)OC1
Reactant: CCCCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC1COC(c2ccc(CCCCCCC)c(F)c2F)OC1
Reaction time: 8 h

Procedure:
n-Butyllithium (3.4 cm3, 10.0M in hexanes, 34mmol) was added dropwise to a stirred, cooled (-78° C.) solution of compound from Example 115 (mixture with isomers) (11.2 g, 34 mmol) in dry THF (100 cm3) under an atmosphere of dry nitrogen. The mixture was maintained under these conditions (3 h) then a solution of 1-iodoheptane (7.7 g, 34 mmol) in dry THF (20 cm3) was added dropwise at -78° C. The temperature of the reaction mixture was allowed to reach room temperature overnight. After separation, the aqueous layer was extracted with diethyl ether (2×150 cm3), the combined ethereal layers washed with water (2×150 cm3) and dried (MgSO4). The solvent was removed in vacuo to give the product as a brown oil which was purified by distillation under reduced pressure and recrystallised several times from methanol to remove the cis-isomer.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2([C:12]3[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=3[O:14][CH2:15][CH2:16][N:17](C)[C:18](=O)OCC3C=CC=CC=3)[CH2:11][CH2:10]2)[C:5](=[O:33])[N:4]([C:34]2[CH:39]=[C:38]([C:40](=[O:45])[NH:41][CH:42]3[CH2:44][CH2:43]3)[CH:37]=[C:36]([F:46])[C:35]=2[CH3:47])[CH:3]=1.C([O-])=O.[NH4+].O.C(O)=O>C(O)C.[Pd]>[CH:42]1([NH:41][C:40](=[O:45])[C:38]2[CH:39]=[C:34]([N:4]3[CH:3]=[CH:2][N:7]=[C:6]([NH:8][C:9]4([C:12]5[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=5[O:14][CH2:15][CH2:16][NH:17][CH3:18])[CH2:11][CH2:10]4)[C:5]3=[O:33])[C:35]([CH3:47])=[C:36]([F:46])[CH:37]=2)[CH2:44][CH2:43]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC2(c3ccccc3OCCN(C)C(=O)OCc3ccccc3)CC2)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)cc(F)c3C)c2=O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a slurry of benzyl [2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate (15.0 g, 19.0 mmol), ammonium formate (4.9 g, 76.0 mmol) and 5% Pd/C (8.20 g, 3.8 mmol) in ethanol (150 mL) was charged water (6.8 mL, 379.8 mmol) and formic acid (1.49 mL, 388.0 mmol). The mixture was heated to 50° C. and held for 1 h before being cooled to 20° C. The mixture was filtered through a Celite pad, and the filter cake washed with ethanol (3×15 mL). The filtrates were combined and distilled (60° C. jacket temperature) to adjust the concentration of the solution to 2 rel. vol. with respect to the starting benzyl [2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate. Isopropyl acetate (75 mL) was charged and the mixture cooled to 40° C. at 0.25° C./min. After seeding with the subtitle compound hydrobromide salt, the mixture was cooled further to 20° C. at 0.25° C./min. Isopropyl acetate (75 mL) was charged and the slurry cooled to 5° C. before being held for 1 h. The slurry was then filtered. The filter cake was washed with isopropyl acetate (15 mL) and dried under vacuum on the filter until de-liquoring was complete. The filter cake was then slurried in ethyl acetate (150 mL) and aq. sodium hydroxide (1 M, 150 mL) charged. The biphasic mixture was stirred at 20-25° C. until full dissolution was achieved (˜30 min). The phases were separated and the upper organic phase washed with aq. sodium hydroxide (1 M, 150 mL). The solution was then heated to 50° C. and distilled under reduced pressure to double the concentration (75 mL distillate removed). The solution was heated to 70° C. and heptane (56 mL) charged slowly. After seeding with the subtitle compound, the mixture was cooled to 25° C. at 0.25° C./min. Further heptane (19 mL) was charged slowly and the slurry cooled to 5° C. before being held for 1 h. The slurry was then filtered. The filter cake was washed with heptane (15 mL) and dried under vacuum at 40° C. to afford N-cyclopropyl-3-fluoro-4-methyl-5-[3-[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropylamino]-2-oxo-1(2H)-pyrazinyl]benzamide (6.0 g, 96.0% w/w).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:14]([C:13]3[CH:16]=[CH:17][C:18]([OH:19])=[C:11]([Cl:10])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: Nc1cc(Br)cnc1N
Product: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1Cl

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 3-chloro-4-hydroxybenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N:40]1[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(F)c4)cnc32)cc1
Yield: 93.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (150 mg, 0.206 mmol) was deprotected in TFA/DCM (1/1 ml) to afford 120 mg (93% yield) of the titled compound. MS: m/z=625.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH3:28])[N:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[OH:16][CH:15]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][CH2:27][CH3:28])[N:18]=1)[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1
Reactant: CCCn1nc(C(O)c2cccc(OCc3ccccc3)c2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCn1nc(C(O)c2cccc(O)c2)c2ccccc21
Yield: 35.4 %

Procedure:
A mixture of [3-(benzyloxy)phenyl]-(1-propyl-1H-indazol-3-yl)methanol (0.067 g, 0.18 mmol.), ammonium formate (0.09 g, 1.17 mmol) and 10% palladium on carbon (0.09 g) in 10 mL ethanol was heated at reflux for 18 hours. The reaction was filtered (celite) and the cake washed with excess ethanol. The filtrate was concentrated in vacuo. The crude product was purified by HPLC [column: silica gel 150×12 mm (Biotage) at 10 mL/min with methyl-t-butyl ether/hexane, gradient elution, 1:9 to 1:1 over 15 min) to give the title compound (0.018 g) as a white solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:17]1[CH:18]=CC2N(O)N=[N:23][C:21]=2[CH:22]=1.C(Cl)CCl.N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14](=[O:16])[N:23]1[CH2:18][CH2:17][CH2:22][CH2:21]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 50 mL round-bottomed flask was charged with Boc-D-tert-leucine (1.00 g, 4.32 mmol), HOBT (728 mg, 4.76 mmol), EDC (912 mg, 4.76 mmol) and pyrrolidine (0.57 mL, 6.89 mmol). Then added DMF (18 mL) followed by N,N-diisopropylethylamine (1.1 ml, 6.3 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with H2O and extracted with Et2O (2×). The combined organic layers were washed twice with H2O and once with brine then dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography over 40 g SiO2 with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 1.0 g (83%) of (R)-tert-butyl 3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=O)[O:24]C(C)(C)C)[CH3:21])=[CH:16][C:15]=3[F:32])[C:12]=2[F:13])[CH:9]=1)[CH3:2].Cl.[C:34](OCC)(=O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:24])[CH3:34])[CH3:21])=[CH:16][C:15]=3[F:32])[C:12]=2[F:13])[CH:9]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1ccc2c(F)c(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3F)nn2c1
Agent: Cl
Product: CCOc1ccc2c(F)c(-c3ccc(OC[C@H](C)NC(C)=O)cc3F)nn2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl {(1S)-2-[4-(6-ethoxy-3-fluoropyrazolo[1,5-a]pyridin-2-yl)-3-fluorophenoxy]-1-methylethyl}carbamate (52 mg), 4 M hydrogen chloride/ethyl acetate (2 mL), and ethyl acetate (1 mL) was stirred at room temperature for 6 hr. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (1 mL) and acetic anhydride (1 mL). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (18.7 mg) as white crystals.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][C:18]1[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=1[CH:20]=[N+:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:20]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1C=[N+]1CCCC1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cl-]
Product: Cc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-methyl-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 25.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.N1C=CN=C1.[C:29]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:29]([Si:33]([CH3:35])([CH3:34])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1(C)c2cc(O[Si](C)(C)C(C)(C)C)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
The DMF solution of 8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 100 mg, 0.331 mmol), imidazole (67.5 mg, 3 eq.) and tert-butylchlorodimethylsilane (92.4 mg, 1.5 eq.) was stirred overnight at room temperature. To the reaction solution, saturated aqueous solution of sodium hydrogen carbonate was added followed by extraction with tert-butylmethyl ether. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white solid, 170 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[I:26]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:26][C:8]1[CH:7]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COc1ccc(-c2ccc(C(=O)OCc3ccccc3)nc2C)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)OCc3ccccc3)nc2C)cc1I

Procedure:
Benzyl 5-(4-methoxyphenyl)-6-methylpyridine-2-carboxylate (150 mg, 0.45 mmol), iodine (228 mg, 0.898 mmol), silver sulfate (402 mg, 1.29 mmol) were stirred in methanol (3 mL) at room temperature overnight. More iodine (57 mg, 0.22 mmol) and silver sulfate (100 mg, 0.32 mmol) were added into reaction mixture after 25 hours. Added aqueous NaHSO3 solution (sat., 20 mL) into the reaction mixture after additional 1.5 hours to quench the reaction. The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration to afford a clear oil. The crude oil was purified by preparative TLC on SiO2 (eluted with 30% ethyl acetate in hexanes) to afford benzyl 5-(3-iodo-4-methoxyphenyl)-6-methylpyridine-2-carboxylate. LCMS calc.=459.03; found=460.17 (M+1)+.
Reaction SMILES: [CH3:1][CH2:2]N(C(C)C)C(C)C.[C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:32])=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:17]=1)#[N:11].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[O:32][C:1](=[CH2:2])[N:18]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[C:16]=2[CH:17]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C#N)ccc2O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C1Oc2ccc(C#N)cc2N1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
Hünig's base (1 mL, 5.73 mmol) was added to a solution of 1,1-dimethylethyl 4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate (D32, 977 mg, 3.08 mmol) in dichloromethane (20 mL) at rt under argon. The reaction was cooled to 0° C. and triphosgene (373 mg, 1.26 mmol) was added. The reaction was then stirred for 30 min at 0° C. and quenched with saturated aqueous NaHCO3 (20 mL) before being partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow oil. The crude residue was purified via chromatography (silica, Biotage 40+S column, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-(5-cyano-2-methylidene-1,3-benzoxazol-3(2H)-yl)-1-piperidinecarboxylate (D33, 1.22 g, 92% yield, 82% purity by LC-MS) as a yellow oil.