Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][N:4]([CH:21]([CH3:23])[CH3:22])[C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]2)[S:10][CH:11]=1)=[O:6])#[N:2].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:14]1[CH2:13][N:12]([C:9]2[S:10][CH:11]=[C:7]([C:5](=[O:6])[N:4]([CH2:3][C:1]#[N:2])[CH:21]([CH3:22])[CH3:23])[N:8]=2)[CH2:15]1)(=[O:27])[CH3:25]
Reactant: CC(C)N(CC#N)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(CC#N)C(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of 1-[4-(N-cyanomethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (635 mg, 1.77 mmol) (obtained as described in Reference Example 49(5)) in dimethylformamide (19 ml) was added potassium thioacetate (1.21 g, 10.6 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 3-acetylthio-1-[4-(N-cyanomethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidine (344 mg, yield 57%) as a pale brown solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(CC)CC>C1COCC1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][NH:7][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 94.5 %

Procedure:
Methanesulfonyl chloride (4.10 g, 35.8 mmol) was added to a suspension of ethyl 4-aminobutyrate hydrochloride (6.00 g, 35.8 mmol) and Et3N (10.8 mL, 77.4 mmol) in THF (230 mL). The resulting suspension was stirred at room temperature for 43 h. The reaction mixture was filtered and the filtrate was concentrated. Flash chromatography (1:1 EtOAc:hexanes to EtOAc) afforded the title compound (7.08 g). 1H NMR (400 MHz, CDCl3) δ 4.51 (s, 1H), 4.12 (q, 2H), 3.18 (q, 2H), 2.94 (s, 3H), 2.40 (t, 2H), 1.85–1.92 (m, 2H), 1.24 (t, 3H); MS 210 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[C:4]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:3]=1.C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:6][C:23](=[O:24])[C:14]3[N:13]2[CH:17]=[CH:16][N:15]=3)=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Temperature: 25 °C
Yield: 69.3 %

Procedure:
4-Bromo-2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (12.65 g, 0.0413 mol) is stirred under nitrogen with N,N-carbonyldiimidazole (13.8 g, 0.0825 mol) at 135° C. for 7 hours. After being cooled down to room temperature, the mixture is filtered to yield a grey solid, which is suspended in ethyl acetate (500 mL) and stirred at reflux for 10 minutes. After filtration at room temperature, the solid is washed with ethyl acetated (200 mL) and dried under vacuum to afford the title compound as a grey powder (9.5 g, 69.2%)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4(OCC[O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O>CC(C)=O.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc3c(c2)OCO3)CC1
Yield: 94.9 %

Procedure:
A solution of 8-(1,3-benzodioxol-5-yl)-1,4-dioxaspiro[4.5]decan-8-ol (5 g, 18 mmole) in 75 ml acetone, 1 ml 12N HCl, and 50 ml water, was stirred for 2 hr. After dilution with an additional 50 ml water the solid was collected to give the product (4.0 g, 95%, mp: 166°-168° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1=[O:18])[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]4=[O:18])=[C:2]([CH3:1])[CH:3]=3)[CH3:28])=[N:26][C:22]=2[CH:21]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCCOC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCCOC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then acidifying with TFA and purification of the residue by chromatography (preparative HPLC).
Reaction SMILES: [CH2:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]([NH2:28])([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[OH:4][CH:2]([CH2:1][O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH2:3][NH:28][C:17]([CH3:27])([CH3:16])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: C1C2CC3CC1CC(OCC1CO1)(C2)C3
Product: COc1ccc(CC(C)(C)NCC(O)COC23CC4CC(CC(C4)C2)C3)cc1
Yield: 53.4 %

Procedure:
Using the method of Example 16, supra, 1-adamantyl glycidyl ether (350 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 207 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 338 (M+1, 0.1), 372 (0.3), 266 (65), 163 (1), 135 (100), 121 (16); 1H-NMR (CDCl3) δ7.02 (2H, d, J=8.3), 6.74 (2H, d, J=8.6), 3.70 (3H, s), 3.64 (1H, m), 3.38 (4H, m), 2.71 (1H, dd, J=11.5 and 4.0), 2.57 (3H, m), 2.06 (3H, broad s), 1.64 (6H, broad s), 1.53 (6H, m), 1.13 (4H, apparent t, J=6.9), 0.98 (3H, s), 0.97 (3H, s); 13C-NMR (CDCl3) δ157.8, 131.2, 130.0, 113.1, 77.8, 70.5, 69.4, 54.9, 52.8, 46.3, 44.6, 32.0, 26.7, 26.6, 25.6, 23.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[NH:39][N:38]=[N:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:39]4[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:36][N:37]=[N:38]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: c1ccc(-c2cnn[nH]2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4nncc4-c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-1H-[1,2,3]triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Mg].[C:10]([C:12](=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2([CH:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C1(c2cccc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-chloro-3-iodobenzene (14.1 g, 59.28 mmol) in diethyl ether (12 ml) was added dropwise to a mixture of magnesium turnings (1.59 g, 65.4 mmol) in diethyl ether (50 ml) at room temperature. When the Grignard reaction was complete, the resulting organomagnesium reagent was added dropwise to a stirred mixture of compound 16a (5.0 g, 17 mmol) and cuprous iodide (800 mg, 4.2 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. The reaction mixture was stirred 1 hour at 0° C. and then quenched with saturated ammonium chloride solution. Ethyl acetate (500 ml) was added and the mixture was washed successively with saturated ammonium chloride, water and brine. The organic layer was dried and concentrated and the resulting crude material was purified by column chromatography on silica gel eluting with 4:1 hexane:ethyl acetate. This afforded tert-butyl 4-(3-chlorophenyl)-4-(1-cyano-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (16b) as an oil (5.2 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.37-7.26 (m, 4H), 3.99 (br.q, 2H, J=6 Hz), 3.91 (br m, 2H), 3.58 (s, 1H), 2.88 (br.m, 2H), 2.52 (ddd, 2H, J=6, 4, 3 Hz), 2.04 (m, 2H), 1.43 (s, 9H), and 1.06 (t, 3H, J=6 Hz). ES-LCMS m/z 429 (M+Na+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CN1CCCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCCN(C)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-methyl-1,4-diazepane (0.144 mL, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) in dichloromethane (4.00 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (274 mg, 94%) as a white solid. This was used directly with no further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([CH3:15])[C:9]1=[O:16].[Cl:17][CH2:18][C:19](O)=[O:20].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([CH3:15])[C:9]1=[O:16])=[O:20]
Reactant: CC1=C(C)C(=O)N(CCCCCCO)C1=O
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(CCCCCCOC(=O)CCl)C1=O

Procedure:
A mixture of 67.6 g (0.30 mole) of N-(6-hydroxyhexyl)dimethylmaleimide, 34.0 g (0.36 mole) of chloroacetic acid, 3.5 g of concentrated sulfuric acid and 300 ml of toluene is reacted and worked up as described in Example 1. The residue consists of 86.6 g of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[C:15](O)=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)Cl.C(Cl)(=O)[C:22](Cl)=[O:23].Cl>Cl[Ti](Cl)(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:22](=[O:23])[CH2:15][CH:10]1[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cccc(C2CCCCC2C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)C1CCCCC1CC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
Combine 2-(3-methoxy-phenyl)-cyclohexane carboxylic acid (11.50 g, 46.3 mmol), methylene chloride (200 mL), catalytic DMF (4.0 mL) and slowly add oxalyl chloride (4.8 mL, 55.6 mmol), stir at room temperature. After 1.5 hours, at 0° C. add TiCl4 (12.7 mL, 115.78 mmol) and let reaction warm to room temperature. After 3.5 hours, quench reaction with ice water and add 5N HCl. Allow reaction mixture to stir for 30 minutes then extract with ethyl acetate and wash with sodium bicarbonate solution (aq), then Brine. Dry the organic phase with anhydrous sodium sulfate then concentrate and flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (9.91 g, 93%) as a yellow oil. TLC Rf=0.26 in 5:1 hexanes:ethyl acetate 1H NMR (CDCl3): 8.01 (d, 1H, J=8.8 Hz), 6.83 (m, 1H), 6.72 (m, 1H), 3.86 (s, 3H), 2.89 (m, 2H), 2.45 (m, 2H), 1.60 (m, 8H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][N:11]([CH3:19])[C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.C(O)C>COCCOC>[CH3:10][N:11]([CH3:19])[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:18]=2)[CH:17]=1
Reactant: CN(C)c1ccc(N)nc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cn2cc(N(C)C)ccc2n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
215 μl of ethyl bromopyruvate are added to a suspension of 0.2 g of 5-dimethylaminopyridine-2-amine in 3 ml of DME. The reaction mixture is stirred at 20° C. for 16 hours, then, after addition of 3 ml of ethanol, for 16 hours at reflux and, finally, concentrated under reduced pressure. The residue is filtered on a cartridge comprising 15 g of silica, elution being carried out with a mixture of dichloromethane and methanol (98/2). The fractions comprising the expected product are combined and washed with a saturated sodium bicarbonate solution. The organic phase is dried and concentrated to dryness under reduced pressure to give 76 mg of ethyl 6-dimethylamino-imidazo[1,2-a]pyridine-2-carboxylate in the form of a green oil used as is in the continuation of the synthesis.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:26][OH:27])=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:20]2[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: Cc1cnc(CO)c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnc(COc2nc(N)nc(-n3cccn3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 3,5-dimethyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
In a round-bottomed flask, a solution of the crude cinnamoyl chloride (25.2 g) in dichloromethane (50 ml) was added to a stirring mixture of pyridine (14.4 g, 182 mmol) and 4-dimethylaminopyridine (1.44 g, 11.8 mmol) in dichloromethane (100 ml) at 0° C. and stirred for 15 minutes before a solution of 4-fluoroaniline (13.2 g, 118.79 mmol) in dichloromethane (50 ml) was added over 20 min. After being stirred for 3 h at room temperature, the mixture was quenched with water (500 ml) and extracted with dichloromethane (3×150 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by silica gel chromatography using 1-5% ethyl acetate in petroleum to elute. The product-containing fractions were combined to afford N-(4-fluorophenyl)cinnamamide as a light yellow solid (17.8 g, 61%); (ES, m/z): [M+H]+ 242; 1H NMR (300 MHz, CDCl3): δ 10.28 (s, 1H), 7.70-7.75 (m, 5H), 7.39-7.65 (m, 3H), 7.15 (t, J=9.0 Hz, 2H), 6.79 (d, J=15.6 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:15]([C:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[NH:12][CH:13]=1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Product: O=C(NCc1ccccc1)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 7.6 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 40 μL (0.36 mmol) of benzylamine. After recrystallization from methanol, 8 mg (8%) of N-(benzyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH3:23].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH3:23])=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CC
Yield: 79.5 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (110c) (0.35 g, 1.45 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.11 g, 0.6 mmol), WSC hydrochloride (0.38 g, 2 mmol), HOBt (0.13 g, 1 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 3/2, 2/1) to obtain 0.23 g of the title compound as a colorless solid (80%).
Reaction SMILES: Cl[CH:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]1[CH:17]=[O:18].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:11]1([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]([CH:17]=[O:18])[CH:2]2[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC1c2cccnc2N(c2ccccc2)C1Cl
Reactant: C1CNCCN1
Product: O=CC1c2cccnc2N(c2ccccc2)C1N1CCNCC1
Yield: 63 %

Procedure:
2-Chloro-1-phenyl-1,3-dihydropyrrolo[2,3-b]pyridine-3-carboxaldehyde is reacted with piperazine as described in Example 2 to give l-phenyl-2-(piperazin-1-yl)-1,3-dihydropyrrolo[2,3-b]pyridine-3-carboxaldehyde (63% yield).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.S(=O)(=O)(O)O>[C:8]1([CH2:7][CH:6]([OH:2])[C:14]([OH:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A solution of 0.829 g of sodium nitrite in 4.2 ml of water is added dropwise at 0° C. to a suspension of 1.6 g of phenylalanine in 5.3 ml of sulfuric acid (2.5N). The reaction mixture is stirred for 2 hours at 0° C. and then for 17 hours at room temperature. The reaction mixture is extracted with twice 100 ml of ethyl acetate. The pooled organic phases are washed with 100 ml of a saturated sodium chloride solution in water. 1.2 g of yellow crystals are obtained after drying.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29](I)=[C:28]([CH:31]4[CH2:33][CH2:32]4)[N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][CH:26]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[CH:63][CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[C:28]([CH:31]4[CH2:33][CH2:32]4)[N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][CH:26]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cnc3c(c2)c(I)c(C2CC2)n3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)c(C2CC2)n3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 122.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-2-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 36) (110 mg, 0.1610 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (61 mg, 0.1771 mmol) in sodium carbonate (51 mg, 0.4831 mmol), Pd(PPh3)4 (10 mg, 0.0080 mmol) and DME/water (3/1 ml) to afford 150 mg of the crude product which was taken as such for next reaction.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([N+:12]([O-])=[O:13])([CH3:11])[CH3:10].C(O)(=O)C>C(O)C.[Zn]>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N+:12]([C:9]([CH3:11])([CH3:10])[CH3:8])[O-:13]
Reactant: O=Cc1ccc[nH]1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1ccc[nH]1

Procedure:
To a suspension of pyrrole-2-carbaldehyde (277.8 mg, 2.92 mmol), 1,1-dimethylnitroethane (601.1 mg, 5.83 mmol) and zinc (572.5 mg, 8.76 mmol) in ethanol (4.0 ml) was added acetic acid (1.05 g, 17.5 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=1/1-2/3).