Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[CH:13]=[C:12]([NH:18][CH2:19][C:20]4([C:23]([F:26])([F:25])[F:24])[CH2:22][O:21]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>ClCCl>[F:24][C:23]([F:26])([F:25])[C:20]([CH2:22][NH:30][CH2:27][CH2:28][CH3:29])([OH:21])[CH2:19][NH:18][C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: CCCN
Reactant: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccc(F)cc3)c2c1
Solvent: ClCCl
Product: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-methyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine (1.4 g, 3.84 mmol) in dichloromethane (50 ml) was added n-propylamine (20 ml, 243 mmol). The reaction was stirred at room temperature overnight and then evaporated in vacuo. The crude product was purified on a 70 g silica Bond Elut cartridge using a 0-50% ethyl acetate in dichloromethane gradient over 60 minutes to give the title compound (0.4 g).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(C(C)C)C(C)C.[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([OH:45])=O)[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([NH:4][CH2:2][CH3:3])=[O:45])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)CC)n3CC2CCOCC2)c1
Yield: 60.4 %

Procedure:
Following the same procedure in Example 24, Step A, using ethylamine hydrochloride (29 mg, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 53 mg (61%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.77 (t, J=7.42 Hz, 3 H), 1.15 (t, J=7.32 Hz, 3 H), 1.39-1.57 (m, 4 H), 1.58 (s, 6 H), 1.94 (q, J=7.68 Hz, 2 H), 2.19-2.37 (m, 1 H), 3.24-3.40 (m, 4 H), 3.83-3.94 (m, 2 H), 4.41 (d, J=7.23 Hz, 2 H), 7.92 (d, J=8.8 Hz, 1 H), 7.99 (dd, J=8.8, 1.4 Hz, 1 H), 8.04 (s, 1 H), 8.34 (d, J=1.17 Hz, 1 H), 8.74 (s, 1 H); MS (ESI) (M+H)+=488.0; Anal. Calcd for C24H33N5O4S+0.9 TFA+0.3H2O (595.65): C, 52.02; H, 5.84; N, 11.76. Found: C, 52.01; H, 5.66; N, 11.91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[CH:28]=[CH:29][N:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:33])([F:34])[F:32])=[CH:20][CH:21]=2)[C:26]1=[O:30])[CH3:13]
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 22 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.0 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.23 g of 1-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2(1H,3H)-imidazolone, 0.43 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2(1H,3H)-imidazolone was obtained as colorless plates.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
2,4-Dichloropyridine (4.44 g, 30.0 mmol) and potassium carbonate (8.28 g. 60.0 mmol) in dimethylformamide (60 mL) was purged with nitrogen for 10 min. 4-Aminothiophenol (3.76 g, 30.0 mmol) was added and the mixture stirred under nitrogen at room temperature for 18 h. Water (300 mL) was added and the slurry stirred for 30 min. The resulting solid was filtered, washed with water and vacuum dried at room temperature. Recrystallization from ethyl acetate (35 mL), filtered hot, then cooled gave 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (3.946 g, 56% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1>>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using 2-aminoethyl-methyl-sulfone (258 mg, 2.096 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-thiophenesulfonamide (100 mg, 0.210 mmol) the title compound was obtained as a light yellow solid (20 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H) 8.07 (d, J=4.9 Hz, 1H) 7.82-7.92 (m, 1H) 7.46-7.52 (m, 1H) 7.37-7.46 (m, 1H) 7.28-7.36 (m, 1H) 7.12-7.25 (m, 3H) 7.04-7.12 (m, 1H) 6.04-6.14 (m, 1H) 3.55-3.69 (m, 2H) 3.30-3.37 (m, 3H) 2.97 (s, 3H) 1.32 (d, J=6.8 Hz, 6H). MS (ESI): 564.1[M+H]+.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:21]#[N:22])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+].CO>>[C:21]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:7])[N:9]=1)#[N:22]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(OC)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-methoxy-isoquinoline-3-carboxylic acid butyl ester (104 mg, 0.35 mmol), glycine (523 mg, 6.97 mmol), and a 0.5 M solution of sodium methoxide in methanol (13.2 mL, 6.6 mmol) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 mL) and the solution was extracted with methyl tert-butyl ether (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (10 mL). The resulting white precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (82 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.53 (t, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.57 (m, 2H), 4.02 (d, J=6.2 Hz, 2H), 3.98 (s, 3H); MS: (+) m/z 302.00 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH:15]([CH3:17])[CH3:16]>>[CH:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:17])[CH3:16]
Reactant: C1CNCCN1
Reactant: CC(C)Oc1ccccc1Br
Product: CC(C)Oc1ccccc1N1CCNCC1

Procedure:
The title compound was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 1-bromo-2-isopropoxy-benzene. LRMS (ESI+): 221.4 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:11])=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[CH:12](O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][CH:12]=[N:10][C:5]=2[C:4]=1[CH3:11]
Reactant: O=CO
Reactant: COc1ccc(N)c(N)c1C
Product: COc1ccc2[nH]cnc2c1C
Temperature: 60 °C
Yield: 84 %

Procedure:
A mixture of 4-methoxy-3-methyl-l,2-benzenediamine (2.8 g, 18A mmol) and formic acid (30 mL) was heated at 60° C. for 30 minutes. The formic acid was removed under reduced pressure and the product was partitioned between chloroform and water containing sufficient sodium hydroxide to basify the solution. After evaporation of the solvent the crude product was chromatographed (methanol:chloroform) to give 2.55 g (84%) of 5-methoxy-4-methyl-1H-benzimidazole.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][NH2:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[Br:1][C:2]1[C:3]([NH:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine 3.2 g (0.0135 mole) in ethanol 80 mL was added Hunig's base 3.0 mL followed by the addition of a solution of N-(tert-butoxy carbonyl)-1,2-diaminoethane 2.5 g (0.0156 mole) in 20 mL ethanol. The contents were stirred overnight for 20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (200 mL) and water (100 mL) was added and the layers separated. The organic layer was dried with magnesium sulfate and then concentrated under vacuum. Column chromatography on silica gel using hexane/ethyl acetate (0-60%) afforded tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. 1HNMR (d6-DMSO) 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M+H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.COCCOC.C([O-])(O)=O.[Na+]>CCOC(C)=O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[C:10]([Cl:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1cccnc1Cl
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: COCCOC
Solvent: CCOC(C)=O
Product: Clc1nccc(-c2cccnc2Cl)n1
Temperature: 90 °C

Procedure:
To 2,4-dichloropyrimidine (2.00 g, 13.4 mmol), 2-choropyridine-3-boronic acid (3.16 g, 20.1 mmol) and Pd(PPh3)4 (1.55 g, 1.30 mmol), was added DME (30.0 ML) and 1 M NaHCO3 (13.0 mL). The resulting mixture was heated to 90° C. for 17 hours, then diluted with EtOAc and extracted with saturated sodium carbonate, water, and brine. The organics were dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether and dried to yield the desired product. MS m/z=226 [M+H]+. Calc'd for C9H5Cl2N4: 225.12.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:28]([CH2:34][CH2:35][CH3:36])=[N:27][C:21]=3[C:22]([NH2:26])=[N:23][C:24]=2[CH:25]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:27]=[C:28]([CH2:34][CH2:35][CH3:36])[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)=[CH:25][C:24]=2[N:23]=1
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNC(=O)c4cccnc4)ccc3c2n1CC(C)C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
Nicotinoyl chloride hydrochloride (0.23 g, 1.29 mmol) was added in one portion to a solution of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.460 g, 1.29 mmol) and triethylamine (0.383 mL, 2.75 mmol) in chloroform (15 mL), and the reaction was stirred for 16 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and stirred for 30 minutes. The aqueous layer was separated and extracted with chloroform. The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale yellow oil was triturated with acetonitrile, which was removed under reduced pressure. The resulting solid was recrystallized from acetonitrile to yield 0.310 g of N-{3-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}nicotinamide as off-white, granular crystals, mp 172-174° C.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:37])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:39][C:40]([F:47])([C:43]([F:46])([F:45])[F:44])[CH2:41][NH2:42]>ClCCl.C(OC(=O)C)C>[CH:26]1([CH2:25][N:22]2[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:42][CH2:41][C:40]([F:47])([F:39])[C:43]([F:46])([F:45])[F:44])[CH3:14])=[O:37])[C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=3[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]2=3)[CH2:28][CH2:27]1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Yield: 98 %

Procedure:
0.61 g (1.18 mmol) carbonic acid (S)-1-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester 4-nitro-phenyl ester and 2.5 ml 2,2,3,3,3. pentafluoropropylamine were stirred at room temperature over night. Chromatography on silicagel with dichloromethane/ethylacetate (100-70/0-30) yielded 0.61 g (98%) (2,2,3,3,3-pentafluoro-propyl)-carbamic acid (S)-1-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester as white solid; MS: m/e: 526.0 (M+H+), [α] 589=−940° (1.1% in MeOH).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:22][CH2:23][OH:24]>C(O)C.O>[OH:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(c1ccc(O)cc1)c1c[nH]c2ccccc12
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(OCCO)cc1)c1c[nH]c2ccccc12

Procedure:
7 g of 3-(p-hydroxybenzoyl)indole and 1.44 g of sodium hydroxide were dissolved in 200 ml of a mixture of ethanol and water (ethanol:water=1:1). 2.85 g of 2-chloroethanol was added to the solution followed by reflux for 3 hours in oil bath. The solvent was evaporated to dryness and the residue was extracted with water-ethyl acetate. The organic layer obtained was purified by column chromatography on silica gel to give a crude product. It was recrystallized from ethyl acetate to obtain 3-[p-(2-hydroxyethoxy)benzoyl]indole (compound 15) in the form of white needle crystals. (Yield: 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) stirred solution of (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.36 mmol) and TEA (1.5 ml, 11.0 mmol) in THF (10 ml) is treated dropwise over 1 minute with pyridine-4 carbonyl chloride hydrochloride (0.935 g, 5.25 mmol). After 5 minutes, the reaction mixture is allowed to warm to room temperature and stirred overnight. The resulting mixture is diluted with EtOAc and washed twice with saturated sodium bicarbonate solution followed by brine. The organic portion is dried (MgSO4) and concentrated in vacuo. The crude product is purified by recrystallisation from EtOAc/iso-hexane to afford the title product. [MH+ 292].
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].Cl[S:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>Cl>[C:40]([C:39]1[CH:38]=[CH:37][C:36]([S:33]([NH:1][CH2:2][C:3]([O:5][C@H:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:18]=2)[CH2:7][C:8]2[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=2[Cl:16])=[O:4])(=[O:35])=[O:34])=[CH:44][CH:43]=1)([OH:42])=[O:41]
Reactant: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc(C(=O)O)cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
(S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (prepared in an analogous manner as described in Scheme 1, Step 1-2) (100 mg, 0.210 mmol) was dissolved in py (2.5 ml). 4-(chlorosulfonyl)benzoic acid (60.1 mg, 0.272 mmol) was added, and the reaction was stirred at RT for 4 hours. The reaction mixture was diluted with HCl 1N and extracted with EtOAc. The organic phase was washed with HCl 1N and brine, dried over Na2SO4 and concentrated under vacuum to give (S)-4-(2-(2-(4-carboxyphenylsulfonamido)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (120 mg, 87% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:8]2[O:12][CH2:11][CH2:10]O2)[CH:5]=[CH:6][CH:7]=1.Br[C:14]1C=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1COCOC>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]2[B:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[O:12][CH2:11][C:10]=2[CH:18]=1
Reactant: COCOCc1cc(Cl)ccc1Br
Reactant: Fc1cccc(B2OCCO2)c1
Product: Fc1cccc(B2OCc3cc(Cl)ccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-fluorophenyl)-[1,3,2]-dioxaborolane and 1-bromo-4-chloro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C[O:12][C:13](=[O:16])[CH2:14][NH2:15]>>[CH:1]1([NH:15][CH2:14][C:13]([OH:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CN
Reactant: O=C1CCc2ccccc21
Product: O=C(O)CNC1CCc2ccccc21

Procedure:
Alternatively, 1-indanone was reductively aminated with glycine methyl ester, followed by saponification of the ester.
Reaction SMILES: O=[C:2]1[CH:7]([C:8](OCC)=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.O.[NH2:21][NH2:22]>C(O)C>[O:9]=[C:8]1[C:7]2[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3][C:2]=2[NH:22][NH:21]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c([nH][nH]c2=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (5.0 g, 18.43 mmol) in ethanol (10 mL) was added hydrazine monohydrate (1.04 g, 20.27 mmol) via syringe. The resulting solution was heated to 80° C. and stirred overnight. A white precipitate formed after stirring overnight. The reaction was cooled to rt and solvent was decanted from the reaction mixture, the solids were dried under vacuum to provide the desired product (3.8 g, 86%). MS (ESI) mass calcd. C11H17N3O3, 239.2. m/z found, 240.2 [M+H]+. 1H NMR (500 MHz, MeOD) δ 4.40 (s, 2H), 3.67-3.54 (m, 2H), 2.40 (t, J=5.6 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[C:29](O)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=[C:26]([O:25][CH3:24])[CH:27]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cc(OC)cc(OC)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,5-dimethoxy-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.80 mmol) and 3,5-dimethoxy benzoic acid (161 mg, 0.87 mmol). The title compound was obtained as powder (62 mg, 16%).
Reaction SMILES: Cl.O1CCOCC1.[C:8]([NH:11][CH2:12][CH2:13][CH:14]([NH:22][C:23]([C:25]1([NH:40]C(=O)OC(C)(C)C)[CH2:30][CH2:29][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([NH:11][CH2:12][CH2:13][CH:14]([NH:22][C:23]([C:25]1([NH2:40])[CH2:30][CH2:29][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:24])[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)NCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)NCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 70 h
Yield: 18.8 %

Procedure:
Hydrogen chloride (4M) in 1,4-Dioxane (0.430 mL, 1.72 mmol) was added to tert-butyl 4-(3-acetamido-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 28) (98 mg, 0.17 mmol) in DCM (4 mL) at 20° C. The resulting suspension was stirred at 20° C. for 70 hours. The reaction mixture was evaporated to dryness. The crude product was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(3-acetamido-1-(4-chlorophenyl)propyl)-4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (15.00 mg, 18.5%) as a white dry film. 1H NMR (399.9 MHz, DMSO-d6) δ 1.42-1.47 (2H, m), 1.79 (3H, s), 1.85 (1H, t), 1.89-1.93 (1H, m), 2.10 (2H, s), 3.00 (2H, t), 3.55 (2H, d), 4.36-4.40 (2H, m), 4.80 (1H, d), 6.58-6.60 (1H, m), 7.16 (1H, t), 7.34-7.39 (4H, m), 7.80 (1H, t), 8.13 (1H, s), 8.39 (1H, s), 11.64 (1H, s) No visible NH2. m/z (ESI+) (M+H)+=470; HPLC tR=1.56 min.