Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[CH:16][C:15]=1[S:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>C(O)C>[OH:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[C:15]([S:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (102 mg, 0.570 mmol) was reacted in ethanol (2 mL) with the product from Example 34b (161 mg, 0.560 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (50 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3H) 2.12 (s, 3H) 2.75 (s, 3H) 6.31 (d, J=6.99 Hz, 1H) 6.61 (s, 1H) 7.15 (s, 1H) 7.29 (d, J=8.46 Hz, 2H) 7.56 (d, J=8.82 Hz, 2H) 7.77 (d, J=8.82 Hz, 1H) 8.39 (d, J=5.52 Hz, 1H) 8.96 (d, J=8.82 Hz, 1H) 9.90 (s, 1H) 10.08 (s, 1H) 10.84 (s, 1H) 14.24 (br s, 1H); MS (ESI+) m/z 431 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([S:16]C(Cl)(Cl)Cl)=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[C:10]2[CH:11]=[CH:12][C:13]([SH:16])=[CH:14][CH:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(c1ccc(SC(Cl)(Cl)Cl)cc1)c1cc(Cl)cc(Cl)c1
Solvent: CO
Product: O=C(c1ccc(S)cc1)c1cc(Cl)cc(Cl)c1
Yield: 73.5 %

Procedure:
In a 100 ml three-neck flask, said 3′,5′-dichloro-4-(trichloro methyl sulfenyl)benzophenone is added into 80 g methanol. The solution is heated with stirring under nitrogen protection to reflux for 5 h, and then is distilled to remove the methanol and all low-boiling-point substances. The residue is recrystallized in a mixed solvent consisting of ethyl acetate and petroleum ether in a weight ratio 1:1 to obtain 21 g yellow-green needle-like crystals with a purity of 98.8%, the yield is 73.5%, and the melting point is 98-99° C. 1H-NMR data (solvent CDCl3): δ3.6808 ppm, s, 1H; δ7.3431, 7.3700 ppm, d, 2H; δ7.5665, 7.5702 ppm, d, 1H; δ7.6033, 7.6065 ppm, d, 2H; 7.6489, 7.6758 ppm, d, 2H.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][N:18]=[C:17]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:28])=[O:29])[CH:25]=[CH:26][C:16]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
Palladium hydroxide (20% wt on carbon, 2.2 g) was added to a solution of 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (22.0 g, 43.9 mmol) in acetic acid (220 mL) under nitrogen. The reaction was evacuated and purged with hydrogen and the reaction warmed to 50° C. for 8 hours. The reaction vessel was recharged with hydrogen gas and stirred at room temperature for 18 hours. The mixture was then filtered through Celite® and the filtrate concentrated to dryness under vacuum. The resulting residue was partitioned between DCM and sodium hydrogen carbonate (sat. aq.), the organic layer dried with sodium sulphate and concentrated under vacuum. The residues were triturated with methanol, filtered, washed with diethyl ether and air dried to afford 16.9 g (82%) of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ: 8.14 (dd, 2H), 7.85 (s, 1H), 7.54 (m, 1H), 7.49 (d, 1H), 7.45 (m, 2H), 6.52 (d, 1H), 4.80 (br s, 1H), 4.05 (s, 2H), 3.86 (m, 1H), 2.97 (t, 2H), 2.61 (m, 2H), 2.03 (d, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH2:14]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23])[CH3:15].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:14]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[CH:22]([NH:23][C:7]1[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=[C:9]([Cl:11])[N:8]=1)[CH2:24][CH:25]([CH3:26])[CH3:27])[CH3:15]
Reactant: CCCCc1cc(Cl)nc(Cl)n1
Reactant: CCOCCCNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(Cl)n1
Temperature: 25 °C

Procedure:
6-Butyl-2,4-dichloropyrimidine (1.0 g), L-leucine-3-ethoxypropylamide hydrochloride (17 mL of a 0.32 M solution in DMSO), and N,N-diisopropylethylamine (3.0 mL) were stirred for 24 h in 20 mL methyl sulfoxide at 60 C. The solution was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed 4 times with 100 mL aliquots of a saturated aqueous solution of sodium chloride. Silica gel chromatography (gradient: 20–40–50–100% ethyl acetate in hexanes) followed by semi-preparative HPLC purification of mixed fractions provided 1.24 g of 2-(6-butyl-2-chloropyrimidin-4-ylamino)-4-methypentanoic acid (3-ethoxypropyl)amide as a colorless oil.
Reaction SMILES: C(O[C:4](=[NH:20])[CH:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([O:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1)[OH:6])C.[C:21]1(N)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>C(O)C>[CH3:19][O:18][C:9]1[CH:8]=[C:7]([CH:5]([C:4]2[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:27]=2)[OH:6])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]=1[O:16][CH3:17]
Reactant: CCOC(=N)C(O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: COc1cc(C(O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.7 g of ethyl(3,4-dimethoxy-5-nitrophenyl)hydroxyacetimidate are dissolved in 500 ml of ethanol, 6.73 g of o-phenylenediamine are added, the mixture is stirred at room temperature for 2 hours and subsequently held at the reflux temperature overnight. After distillation of the solvent, the residue is treated with 50 ml of water, made alkaline with sodium carbonate solution and extracted twice with 250 ml of methylene chloride each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The orange residue obtained is chromatographed on 400 g of silica gel with methylene chloride/ethyl acetate (1:1). From ether/hexane there is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolemethanol in the form of yellowish crystals of m.p. 50° (dec.).
Reaction SMILES: [S].P12([S:14][P:12]3([S:15]P(S[P:8]([S:11]3)([S:10]1)=[S:9])(=S)S2)=[S:13])=S.[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22]S)=[CH:18][CH:17]=1>C1C(Cl)=CC=C(Cl)C=1>[CH2:22]([S:10][P:8]1(=[S:9])[S:11][P:12]([S:14][CH2:22][C:19]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)(=[S:13])[S:15]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: SCc1ccccc1
Agent: [S]
Solvent: Clc1ccc(Cl)cc1
Product: S=P1(SCc2ccccc2)SP(=S)(SCc2ccccc2)S1
Temperature: 190 °C
Yield: 50 %

Procedure:
The method is derived from the reference H. Davy, Sulfur Letters, vol. 3(2) 39, (1985). P4S10 (8.88 g, 0.02 mol) is mixed with 30 ml of dichlorobenzene until this solvent refluxes (160° C.). Benzylthiol (16.5 ml; 0.14 mol) is slowly added to the solution over 40 minutes, while increasing the temperature up to 190° C. The solution becomes clear; the reaction temperature is then reduced to 80° C. The stirring is stopped in order to allow the residual P4S10 to be separated by settling. The solution is filtered in the hot state. The product crystallizes slowly after filtration. The yield is 50%.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][N:3]=1.CN(C=O)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CCOC(C)=O.C1(C)C=CC=CC=1.O>[Si:17]([O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH:10]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1noc2cc(O)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
3-methyl-1,2-benzisoxazol-6-ol (10 g, 67 mmoles) (prepared following M. A. Elkasaby, Indian J. Chem., 1987, 26, 620) and DMF (50 ml) were added to a mixture of tert-butyldimethylsilyl chloride (1.05 eq, 10.6 g), imidazole (2.5 eq, 11.4 g) and DMF (100 ml) under N2. The mixture was then stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under vacuum to give a crude product. Flash chromatography (AcOEt/Toluene 18/85 with 0.1% TEA) gave 6-[(tert-butyl(dimethyl)silyl)oxy]-3-methyl-1,2-benzisoxazole (17.1 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[CH3:11][C:12]([CH3:18])=[C:13](B(O)O)[CH3:14]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:13](=[C:12]([CH3:18])[CH3:11])[CH3:14])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: CC(C)=C(C)B(O)O
Product: CC(C)=C(C)c1cccc(N)c1C#N

Procedure:
Prepared as in Example 1a from 2-amino-6-bromobenzonitrile and 3-Methyl-2-buten-2-ylboronic acid as an orange oil. MS 187 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.Cl[Si:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([Si:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:2]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 66 %

Procedure:
As depicted in Reaction 2, a solution of 4 g (17 mmol) of dibromobenzene in ether was cooled. To the solution were sequentially added n-BuLi and chlorotriphenylsilane. The mixture was allowed to react at room temperature. After completion of the reaction, the reaction mixture was extracted with ether. After the solvent was removed under reduced pressure, the residue was purified by column chromatography to give the title compound. The product was collected by filtration under reduced pressure and dried. Yield: 66%. 1H-NMR (CDCl3, ppm): 7.54-7.5 (m, Ar—H), 7.45 (Ar—H), 7.40-7.35 (m, Ar—H). IR (KBr, cm−1): 1568, 1477-1376, 1110, 810, 727, 698. MS (EI) (Calcd. for C24H19BrSi: 414. Found: 414).
Reaction SMILES: [F-:1].[Cs+].[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1Cl.O>CS(C)=O>[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[F:1]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 94.6 %

Procedure:
Cesium fluoride (11.2 g) was added to a solution of 2-chloro-3-nitrobenzoic acid methyl ester (10.6 g, 49.0 mmol) in DMSO (49 mL), and the mixture was stirred at 140° C. for 40 minutes. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed in series with water and saturated saline, and dried over magnesium sulfate. The title compound (9.23 g, 95%) was then obtained by vacuum concentration as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.Cl.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31]>C(Cl)Cl>[ClH:28].[ClH:8].[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:33]([NH:32][CH2:29][CH:30]=[CH2:31])=[O:34])[CH2:16][CH2:17]2)=[CH:27][CH:26]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: C=CCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 49.6 %

Procedure:
A solution of triethylamine (2.0 g; 20 mmole) in methylene chloride was added dropwise to a mixture of 1-(3-amino-propyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (7.54 g; 20 mmole) and allyl isocyanate (1.66 g; 20 mmole) in methylene chloride. After the addition was completed the mixture was washed with water and the solvent removed. The resulting orange oil was purified on a silica gel column (methylene chloride/methanol; 9:1), precipitated with ethereal hydrochloric acid, and recrystallized from ethanol/water to provide the title compound (2.1 g; 25% yield) as colorless crystals, m.p. 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH2:36]OS(C)(=O)=O)[CH:33]=[CH:32][N:31]=1.CC1C=C(CO)C=CN=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:34]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(COS(C)(=O)=O)ccn1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Agent: Cc1cc(CO)ccn1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3ccnc(C)c3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with methanesulfonic acid 2-methyl-pyridin-4-ylmethyl ester (prepared by mesylation of the commercially available (2-methyl-pyridin-4-yl)-methanol) gave the title compound.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([CH:25]4[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>O1CCOCC1.CC#N>[NH:27]1[CH2:26][CH:25]([C:23]2[O:22][N:21]=[C:20]([C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:11])[CH:14]=3)[N:24]=2)[CH2:28]1
Reactant: Cc1ccc(-c2noc(C3CN(C(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc(-c2noc(C3CNC3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.75 h

Procedure:
To a vial was added tert-butyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F39) (145 mg, 0.3 mmol) and 4N HCl in 1,4-dioxane (2 mL) and CH3CN (1 mL). The reaction was stirred for 45 minutes. The solvent was concentrated and placed under high vacuum. The solid was taken in water/acetonitrile and the pH was adjusted to neutral with an aqueous solution of ammonium carbonate and lyophilized to afford N-(5-(5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (21) which was used directly in the next step. 1H NMR (400 MHz, d6-DMSO) δ 10.85 (s, 1 H), 9.66-9.64 (m, 1 H), 9.42 (bs, 1 H), 9.28 (s, 1 H), 8.10-8.08 (m, 2 H), 8.02-7.98 (m, 1 H), 7.89-7.87 (m, 1H), 7.59-7.53 (m, 2 H), 4.53-4.47 (m, 1 H), 4.36-4.29 (m, 4 H), 2.40 (s, 3 H). MS m/z 375.1 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([F:26])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:27][CH2:28][CH:29]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([F:26])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:27][CH2:28][CH2:29][NH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: O=CCCc1c[nH]c2c(F)cc(F)cc12
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCc2ccc3c(c21)CC(NCCCc1c[nH]c2c(F)cc(F)cc12)CO3
Reaction time: 2 h

Procedure:
To a mixture of (1) (202 mg, 0.99 mmol), 3-(5,7-difluoro-1H-indol-3-yl)propanal ((41), 247 mg, 1.09 mmol) in acetic acid (145 μl, 2.36 mmol) and methanol (10 ml) was added NaBH3CN (126 mg, 2.00 mmol) in portions. Resulting mixture was stirred for 2.0 hr. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 and washed with 1 N NaOH and saturated NaCl. The organic solution was dried over Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting with 70% EtOAc/Hexane to give (18), which was treated with 1 equivalent of etherate HCl to form HCl salt. MS (ES) m/z 412.2.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)(O)=O.S(N)([NH2:26])(=O)=O.S(Cl)(Cl)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>S1(CCCC1)(=O)=O>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)#[N:26]
Reactant: O=C(O)CCCCc1cn(-c2cccnc2)c2ccccc12
Reactant: NS(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: N#CCCCCc1cn(-c2cccnc2)c2ccccc12
Temperature: 0 °C

Procedure:
A suspension of 26.6 g of 3-(4-carboxybutyl)-N-(3-pyridyl)indole and 10.5 g of sulfamide in 90 ml of sulfolane is treated with 11.42 g of thionyl chloride at room temperature under nitrogen. The mixture is heated at 120° until gas evolution ceases and solid p-toluenesulfonic acid monohydrate (1.71 g) is added carefully. After heating an additional 3 hours at 120°, the reaction mixture is cooled, poured onto 200 g of ice and acidified with 130 ml of 1N hydrochloric acid. The aqueous phase is sequentially extracted with ethyl acetate (3×100 ml), made basic with solid sodium bicarbonate and reextracted with ethyl acetate (3×125 ml). The organic extracts are washed with 0.5N sodium hydroxide (5×50 ml), dried over sodium sulfate and evaporated to yield and oil which is chromatographed on 60 g of silica gel to yield 3-(4-cyanobutyl)-N-(3-pyridyl)indole.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([N:7]=[C:8]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[C:37]4=[N:38][CH:39]=[C:40]([Br:42])[CH:41]=[C:36]4[CH2:35][CH2:34][C:33]4[CH:43]=[C:44]([Cl:47])[CH:45]=[CH:46][C:32]3=4)[CH2:27][CH2:26]2)=[O:24])[CH2:18][CH2:17]1)OC1C=CC=CC=1)=[O:6])=[O:3].[NH3:48]>C1COCC1>[NH2:1][C:2]([NH:4][C:5]([NH:7][C:8]([N:16]1[CH2:17][CH2:18][CH:19]([CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[C:37]4=[N:38][CH:39]=[C:40]([Br:42])[CH:41]=[C:36]4[CH2:35][CH2:34][C:33]4[CH:43]=[C:44]([Cl:47])[CH:45]=[CH:46][C:32]3=4)[CH2:27][CH2:26]2)=[O:24])[CH2:20][CH2:21]1)=[NH:48])=[O:6])=[O:3]
Reactant: N
Reactant: NC(=O)NC(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Solvent: C1CCOC1
Product: N=C(NC(=O)NC(N)=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 40 %

Procedure:
Phenyl N-[[(aminocarbonyl)amino]carbonyl]-4-[2-[4-(3-bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-1-piperidine-carboximidate (Formula 16.1) (0.2943 g, 0.462 mmoles) was dissolved in a saturated solution of ammonia in anhydrous THF (80 ml) and the mixture was stirred at 25° C. for 19 h in a sealed vessel. The solution was evaporated to dryness and the residue was chromatographed on silica gel using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (Formula 17.1) (0.2663 g, 40%), ESIMS: m/z 645.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](O)([CH3:24])([CH3:23])[CH3:22].CC(C)N=C=NC(C)C>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:21]([O:19][C:18]([CH:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:13][CH2:14]1)=[O:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)O
Reactant: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CCC(NC(=O)OCc2ccccc2)CC1
Yield: 54.2 %

Procedure:
To a solution of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid (8.0 g, 28.78 mmol) in DCM (35 mL) and DMF (35 mL) is added t-butanol (10 mL, 105.4 mmol) and DMAP (1.4 g, 11.50 mmol). DIPC (10 mL) is added portionwise over 1 h. The resulting mixtures stirs 18 h. The mixture is mounted onto SiO2 and purified by flash chromatography (gradient elution: 0-60% EtOAc/Hep) which affords 5.2 g of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.14 (m, 2 H) 1.30 (m, 2 H) 1.38 (m, 9 H) 1.82 (m, 4 H) 2.07 (m, 1 H) 3.20 (m, 1 H) 3.47 (m, 3 H) 4.99 (m, 2 H) 7.27 (m, 5 H).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6]>ClCCl>[CH3:1][NH:2][S:5]([C:4]([F:10])([F:9])[F:3])(=[O:7])=[O:6]
Reactant: CN
Reactant: O=S(=O)(F)C(F)(F)F
Solvent: ClCCl
Product: CNS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A weighed pressure reactor (available from Parr Instrument Co., Moline, Ill.) is charged with dichloromethane (100 mL) and is then cooled using liquid nitrogen. Methylamine is introduced from a cylinder via a stainless steel tube that is connected to a valve on the reactor. The reactor is periodically weighed, and methylamine is added until 20 g have been added. Trifluoromethanesulfonylfluoride is then introduced into the reactor from a cylinder via a stainless steel tube until 97.9 g have been added. The pressure reactor is then sealed and is placed in a motorized rocker and is rocked and allowed to warm to room temperature. After a period of about 6 hours after the reactor reaches room temperature, it is slowly vented to the atmosphere by opening the valve. The product residue is washed with 10 weight percent aqueous HCl and the organic phase is then dried over MgSO4. The mixture is filtered and the solvent is removed from the filtrate using a rotary evaporator to afford the product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH3:18])=[N:15][NH:16][CH:17]=3)[N:10]3[CH:19]=[CH:20][N:21]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[C:22](#[N:25])[CH:23]=[CH2:24].C(#N)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:18][C:14]1[C:13]([C:11]2[N:10]3[CH:19]=[CH:20][N:21]=[C:9]3[CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:12]=2)=[CH:17][N:16]([CH2:24][CH2:23][C:22]#[N:25])[N:15]=1
Reactant: C=CC#N
Reactant: Cc1n[nH]cc1-c1nc(-c2cnn(C)c2)cc2nccn12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nn(CCC#N)cc1-c1nc(-c2cnn(C)c2)cc2nccn12
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a flask charged with 7-(1-methyl-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.025 g, 0.090 mmol) and acrylonitrile (0.032 mL, 0.49 mmol) was added 1 mL of acetonitrile and DBU (0.027 mL, 0.18 mmol) and the flask was sealed under nitrogen and allowed to proceed at ambient temperature overnight. The reaction was diluted with 3 mL of DCM, loaded directly onto a silica gel column and eluted with 1% MeOH in EtOAc containing 1% NH4OH to afford a mixture of regioisomers from alkylation at N-1 and N-2. The mixture was purified by silica gel chromatography, eluting with a gradient of 1.0-5.0% MeOH in DCM with 0.5% NH4OH to afford the title compound (5.0 mg, 0.0150 mmol, 17% yield). MS (apci) m/z=333.1 (M+H). The structure and regioisomer were confirmed by observed nOe signals.