Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[C:14]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:15][N:16]([CH3:18])[CH:17]=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[C:14]([C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:27])=[N:15][N:16]([CH3:18])[CH:17]=1)=[N+:29]=[N-:30]
Reactant: Cc1noc(COS(C)(=O)=O)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(CN=[N+]=[N-])c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 93.4 %

Procedure:
A mixture of (4-(3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl)-3-methylisoxazol-5-yl)methyl methanesulfonate (35 mg, 0.09 mmol), sodium azide (12 mg, 0.18 mmol) in N,N-dimethylformamide (10 mL) was heated to 80° C. and stirred for 10 h. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=1:3 to give the titled product as a colorless oil (30 mg, 94%). LC/MS: m/z 356 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=9 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J=9 Hz, 2H), 4.37 (s, 2H), 4.09 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[CH3:10][NH:11][C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([O:27]CCC)=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3>>[CH3:10][N:11]([C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([OH:27])=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1cccs1
Product: CN(C(=O)Cc1cccs1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from thiophen-2-yl acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 383.
Reaction SMILES: [CH:1]1([C:6]2([CH3:17])[C:14]3[CH2:13][CH:12]=[CH:11][C:10]=3[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:18][C:19]([CH3:21])=O.N1CCCC1>CO>[C:19](=[C:3]1[CH:4]=[CH:5][C:1]([C:6]2([CH3:17])[C:14]3[CH2:13][CH:12]=[CH:11][C:10]=3[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7]2)=[CH:2]1)([CH3:21])[CH3:18]
Reactant: CC1(C)CCC(C)(C2C=CC=C2)C2=C1C=CC2
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)=C1C=CC(C2(C)CCC(C)(C)C3=C2CC=C3)=C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
7.70 g (34.0 mmol) of the cyclopentadienyltetrahydroindene (Example 5) are dissolved in 70 ml of methanol and cooled to 0° C. The orange-red reaction solution is subsequently treated successively with 2.96 g (51.0 mmol) of acetone and 4.83 g (68.0 mmol) of pyrrolidine. The mixture is stirred at 0° C. for 5 hours and then, in order to complete the reaction, at room temperature for a further 2 hours, before the reaction is terminated by addition of 4 ml of glacial acetic acid. The red, clear reaction solution is hydrolyzed by means of 200 ml of water, and the yellow suspension is extracted 3× with 50 ml of diethyl ether in each case. Repeated washing of the combined organic phases with saturated, aqueous sodium chloride solution and drying over magnesium sulfate give the fulvene as an orange-red, wax-like residue in a yield of 88% (8.00 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].O>CN(C)C(=O)C>[CH3:15][C:13](=[CH2:14])[C:12]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:3]=1)=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(C)c1
Temperature: 2.5 °C

Procedure:
3-Methyl-4-nitroaniline (2.0 g, 13 mmol) in N,N-dimethylacetamide (DMAC) (6 ml) was added dropwise to a cooled solution of methacryloyl chloride (2.0 ml, 20.7 mmol) in a nitrogen atmosphere while the temperature of the reaction mixture was maintained between 0-5° C. The solution was allowed to warm to room temperature and the mixture was stirred over night. The mixture was poured into water (70 ml) and extracted with ethyl acetate (4×40 ml). The organic phase was washed with saturated Na2CO3 (3×20 ml) and water (1×50 ml), dried over Na2SO4 and evaporated. The yield of the crude product was 4.17 g (contains DMA, theoretical yield 2.9 g), and it was used without further purifications. 1H NMR (DMSO-d6): 1.97 (3H, s), 2.55 (3H, s), 5.62 (1H, m), 5.96 (1H, m), 7.80 (2H, m), 8.05 (1H, m), 10.22 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CO.S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[Cl:19][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Yield: 60 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol). The mixture was brought to reflux and sulfuryl chloride (6.8 ml 0.846 mol) dissolved in DCM (50 mL) was slowly added under over 10 min. The reaction mixture was refluxed further for 5 h, upon which the reaction mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO3 solution and water. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>O1CCCC1>[NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[S:19])[NH2:9]
Reactant: NC(=O)c1sccc1N
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1sccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
A solution of 3-aminothiophene-2-carboxamide (4.5 g, 31 mmol) in tetrahydrofuran was treated with Lawesson's Reagent (7.7 g, 190 mmol) and the solution was stirred at room temperature for 18 h. The solvent was removed and the residue purified by chromatography on silica gel using dichloromethane as eluent. The product was obtained as a yellow powder (2.8 g, 56%), m.p. 98-99° C.
Reaction SMILES: [CH3:1][NH2:2].C1(C)C=CC(S(O[C@H:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)(=O)=O)=CC=1>C(O)C>[CH2:18]([N:15]1[CH2:16][CH2:17][C@H:13]([CH2:1][NH2:2])[CH2:14]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Reactant: CN
Solvent: CCO
Product: NC[C@H]1CCN(Cc2ccccc2)C1
Temperature: 140 °C
Reaction time: 0.08 h

Procedure:
An autoclave is initially charged with 6.20 ml of methylamine solution in ethanol and a solution of 2.000 g of (S)-1-benzylpyrrolidin-3-yl toluene-4-sulphonate in 2 ml of ethanol. The reaction solution is subsequently heated to 140° C. over 15 hours. The reaction solution is cooled to room temperature and concentrated to dryness, and the residue is taken up in 10 ml of water. The aqueous solution is extracted with dichloromethane (2×10 ml). The aqueous phase is then admixed with 1 g of potassium carbonate and the suspension is stirred at room temperature over 5 minutes. The solid is filtered off and the filtrate is extracted with dichloromethane (2×10 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The residue is purified by means of flash chromatography (SiO2 60F). The title compound is obtained as a yellow oil. Rf=0.14 (200:20:1 dichloromethane-methanol-25% conc. ammonia).
Reaction SMILES: CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C:45]1=[O:50]>CC(N(C)C)=O>[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]5[N:34]([C:36]([C:39]([F:40])([F:41])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:46][C:45]1=[O:50]
Reactant: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CN1CCNCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1=O
Temperature: 110 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
DIPEA (15.27 mL, 87.69 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (14.19 g, 29.23 mmol) and 1-methylpiperazin-2-one (CAS 59702-07-7, 3.67 g, 32.15 mmol) in DMA (70 mL). The resulting solution was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature, absorbed onto silica, evaporated to dryness and then purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated and the resulting gum was scratched with ether until solid. The solid was stirred in ether (100 mL) for 4 hours then collected by filtration and dried to give 1-methyl-4-[2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one (10.08 g, 68.5%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([CH:18]([O:20][CH2:21][C:22]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH3:19])[N:9]=2)=[CH:4][CH:3]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[C:10]([CH:18]([O:20][CH2:21][C:22]3([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:27][CH2:26][N:25]([CH3:36])[CH2:24][CH2:23]3)[CH3:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(-c2ccc(F)cc2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(C(F)(F)F)cc(-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(4-fluorophenyl)-6-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-4-(trifluoromethyl)pyridine (40 mg, 0.08 mmol), and formaldehyde (37 wt. % solution in water, 0.2 mL, 7.5 mmol) were combined in dichloromethane (2.0 mL) and cooled to 0° C. The reaction was treated with sodium triacetoxyborohydride (74 mg, 0.3 mmol) and a drop of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture was concentrated and purified by preparative HPLC which afforded 10.0 mg (27%) 1H-NMR (CD3OD, 400 MHz) δ 8.09 (m, 1H), 7.93 (m, 1H), 7.14-7.58 (m, 9H), 4.51 (q, 1H), 3.36-3.52 (m, 2H), 2.80-2.93 (m, 2H), 2.59-2.79 (m, 5H), 2.04-2.24 (m, 2H), 1.42 (d, 3H), LC: Tr=1.952 min HPLC Method 1. Mass spec.: 473.36 (MH)+.
Reaction SMILES: [CH3:1]I.[Mg].[CH2:4]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]=[O:22])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[CH2:4]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]([OH:22])[CH3:1])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=CC1Cc2ccccc2N(Cc2ccccc2)C1
Reactant: CI
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)C1Cc2ccccc2N(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
1.12 ml of methyliodide are added dropwise to 0.435 g of magnesium powder, suspended in 50 ml of diethyl ether, in the course of 10 min. After the mixture has been subsequently stirred for 0.5 h, 1.5 g of 1-benzyl-3(R,S)-formyl-1,2,3,4-tetrahydroquinoline, dissolved in 10 ml of diethyl ether, are added dropwise. The mixture is subsequently stirred for 0.5 h and then poured onto ice-water. The crude product extracted with methylene chloride is purified by means of FC over 150 g of silica gel (mobile phase B): Rf (B)=0.31; Rf (D)=0.15.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[N:21]=3)[C:17]([Cl:35])=[CH:16][N:15]=2)[CH2:9][CH2:8]1)(=O)=O.[CH3:36][NH2:37]>CO>[Cl:35][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[N:21]=2)=[CH:19][C:14]([NH:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][NH:37][CH3:36])[CH2:8][CH2:9]2)=[N:15][CH:16]=1
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Reactant: CN
Solvent: CO
Product: CNC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 70 °C

Procedure:
To a scintillation vial containing (trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methyl methanesulfonate (15 mg, 0.029 mmol) was added MeOH (1 ml) and a solution of methyl amine (0.14 ml, 0.289 mmol) in MeOH. The reaction mixture was capped and heated to 70° C. in a oil bath for 16 hr. The resulting solution was concentrated and purified by reverse phase preparative HPLC to yield 5′-chloro-N6-(3-fluorobenzyl)-N2′-(trans-4-((methylamino) methyl)cyclohexyl)-2,4′-bipyridine-2′,6-diamine (8.6 mg, 52%), LCMS (m/z): 454.2 (MH+), retention time=0.64 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.15-1.29 (m, 2H) 1.29-1.42 (m, 2H) 1.67-1.80 (m, 1H) 1.86-1.96 (m, 2H) 2.09-2.21 (m, 2H) 2.71 (s, 3H) 2.90 (d, J=7.04 Hz, 2H) 3.58-3.70 (m, 1H) 4.63 (s, 2H) 6.88 (s, 2H) 6.94 (d, J=7.43 Hz, 1H) 6.96-7.03 (m, 1H) 7.07-7.13 (m, 1H) 7.15-7.21 (m, 1H) 7.29-7.39 (m, 1H) 7.69-7.78 (m, 1H) 8.01 (s, 1H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]=[C:42]=[O:43].O>O1CCCC1>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[NH:41][C:42](=[O:43])[N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:12]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: c1ccc(Nc2nnn(CCCCCCCCOC3CCCCO3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)cc1F)N(c1ccccc1)c1nnn(CCCCCCCCOC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred, cold (-78° C.) solution of (±)N-phenyl-2-[8-[(tetrahydro-2H-pyran-2-yl) oxy]octyl]-2H-tetrazol-5-amine (0.6161 9, 0.001650 mol) in anhydrous tetrahydrofuran (20 mL) was added a 1.6M solution of n-butyl lithium in hexanes (1.0 mL, 0.0016 mol) under a nitrogen atmosphere, and the mixture was stirred. After 2.5 hours, 2,4-difluorophenyl isocyanate (0. 195 mL, 0. 00165 mol) was added dropwise, and the mixture was stirred. After 3 hours the mixture was allowed to warm to room temperature and then stirred 1.5 days. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), and rotoevaporated to an oil. The oil was chromatographed on silica gel (120 g, 230-400 mesh) using chloroform-diethyl ether (24:1, 13×100 mL) as eluent. Fractions containing product were rotoevaporated from diethyl ether to give the title compound as a yellow oil. The oil was dried in vacuo, yield 0.5406 g (64%). 1H NMR (CDC13): δ 10.4 (br s, 1H), 8.3 (m, 1H), 7.5 (m, 3H), 7.4 (d, 2H), 6.9 (m, 2H), 4.6 (m, 1H), 4.5 (t, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.5 (m, 1H), 3.4 (m, 1H), 2.0 (m, 2H), 1.5-1.9 (m, 9H), 1.3 (m, 7H).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:39]([CH3:40])=[CH:38][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33]([CH3:37])[N:32]=[CH:31]5)[CH:23]=3)[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>O1CCOCC1.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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:39]([CH3:40])=[CH:38][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33]([CH3:37])[N:32]=[CH:31]5)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:46]1[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C

Procedure:
The mixture of (S)-2-(7-bromo-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (24 mg, 0.0379 mmol), 4-chlorophenylboronic acid (9 mg, 0.0568 mmol), 2N NaHCO3 (100 μL), Pd(PPh3)4 (4 mg, 0.0038 mmol) in dioxane (2 mL) was heated at 120° C. for 3 hrs. The reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C39H40ClN3O3S: 666.2 (M+H+); Found: 666.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28]#[N:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCCl>[CH2:15]([N:22]1[C:26]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:25][CH:24]=[C:23]1[CH2:27][C:28]#[N:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N#CCc1cccn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 8.43 ml. (0.0663 mole) of p-chlorobenzoyl chloride and 8.8 g. (0.0663 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane is added to a solution of 13.0 g. (0.0663 mole) of 1-benzylpyrrole-2-acetonitrile in 50 ml. of 1,2-dichloroethane at 5° C. over a 5 minute period. The mixture is stirred for 15 minutes, and then heated quickly to reflux for 3 minutes. The reaction mixture is poured into ice-hydrochloric acid and then filtered. The aqueous layer is separated and washed with chloroform. The combined organic solutions are washed successively with N,N-dimethylaminopropylamine solution, dilute hydrochloric acid, and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the oily residue dissolved in benzene-methylcyclohexane and seeded with crystals of 1-benzyl-4-(p-chlorobenzoyl)-pyrrole-2-acetonitrile. After crystallization of the latter substance is complete, the mother liquor is filtered and evaporated and the residue crystallized from methanol. The crystals thus obtained are recrystallized from methanol to give 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile as a yellow solid, m.p. 104-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[O:20][N:19]=[C:18]([CH2:21]Cl)[N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:40]1[CH2:45][C@@H:44]2[CH2:46][C@H:41]1[CH2:42][NH:43]2)=O)(C)(C)C>CC#N.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[O:20][N:19]=[C:18]([CH2:21][N:40]5[CH2:45][CH:44]6[CH2:46][CH:41]5[CH2:42][NH:43]6)[N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1cc(-c2nc(CCl)no2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2nc(CN3CC4CC3CN4)no2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 60 °C
Yield: 58.3 %

Procedure:
To a solution of 2-(4-chloro-benzyl)-5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-7-methyl-2,3-dihydroisoindol-1-one (40 mg, 0.103 mmol) in MeCN (4 mL) was added K2CO3 (0.309 mmol) and (1s,4s)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (31 mg, 0.154 mmol). The mixture was heated at 60° C. overnight. The reaction was cooled and diluted with water, then extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. Column chromatography on silica (1% 2M NH3 in MeOH/CH2Cl2) provided 2-(4-chlorobenzyl)-5-[3-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydroisoindol-1-one as a brown solid (27 mg). 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.99 (s, 1H), 7.37 (d, 2H), 7.26 (d, 2H), 4.77 (s, 2H), 4.30 (s, 2H), 3.94 (dd, 2H), 3.58 (d, 2H), 3.26 (d, 1H), 3.11 (d, 1H), 2.89 (d, 1H), 2.84 (s, 3H), 2.63 (d, 1H), 1.88 (d, 1H), 1.66 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[Br:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(OCC)(=O)C>[Br:23][CH2:24][CH2:25][CH2:26][C:27]([N:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[S:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:28]
Reactant: O=C(Cl)CCCBr
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCCBr)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Yield: 93.2 %

Procedure:
To a mixture of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.08 g), ethyl acetate (20 ml) and aqueous sodium hydrogen carbonate solution (20 ml) is added dropwise a solution of 4-bromobutyryl chloride (0.97 g) in ethyl acetate (5 ml) with stirring under ice cooling. The ethyl acetate layer is washed, dried and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 4-(4-bromobutyryl)-2-(4-chlorophenyl)-3,4-dihyro-2H-1,4-benzothiazine (1.58 g, yield 93%).