Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([CH3:3])[CH3:2].[CH2:11]1[O:15][CH:12]1[CH2:13][CH3:14]>CO>[OH:15][CH:12]([CH2:13][CH3:14])[CH2:11][NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: CCC1CO1
Reactant: CC(C)c1cccc(N)c1
Solvent: CO
Product: CCC(O)CNc1cccc(C(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
10 g (74 mmol) of m-isopropylaniline were dissolved in 100 ml of methanol, and 6.4 g (88.8 mmol) of 1,2-butylene oxide were added thereto. Next, the solution was heated up to 50° C., and then stirred for 1 hour. The solvent was distilled off under reduced pressure, and the solution was then purified through silica gel column chromatography [an eluting solvent: hexane/ethyl acetate=7/3 (v/v)] to obtain 13.2 g of the desired product in an oily state (yield: 86.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:16]([C:20]1[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[N:24][CH:25]=1)[CH:17]([CH3:19])[CH3:18])[C:13](Cl)=[O:14].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][N:7]([CH3:8])[C:13]([N:12]([CH3:11])[CH:16]([C:20]2[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[N:24][CH:25]=2)[CH:17]([CH3:19])[CH3:18])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)C(c1cncnc1C(F)(F)F)N(C)C(=O)Cl
Reactant: CNCc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(c1cncnc1C(F)(F)F)N(C)C(=O)N(C)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 53 %

Procedure:
0.16 g (1.0 mmol) of (4-chlorobenzyl)-methylamine was dissolved in 30 ml of pyridine, and 0.3 g (1.0 mmol) of N-methyl-N-(2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-carbamoyl chloride was dropwise added, followed by stirring at room temperature for 10 hours. To the reaction solution, 50 ml of water was added, followed by extraction with diethyl ether. The obtained organic phase was washed twice with 30 ml of a dilute citric acid aqueous solution, followed by drying over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography (developing solvent/n-hexane:ethyl acetate=8:1 to 3:1) to obtain 0.22 g (yield: 52%) of 1-(4-chlorobenzyl)-1,3-dimethyl-3-[2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-urea as colorless crystals (melting point: 95-98° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[NH3:31]>CC#N>[NH2:31][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: N
Solvent: CC#N
Product: CC(=O)Nc1nc(CCc2ccc(CN)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-{4-{2-[4-(Chloromethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (150 mg) was suspended in CH3CN (6 ml), and then 28% ammonia solution (0.4 ml) was added to the suspension at 0° C. The reaction mixture was stirred at r.t. for 16 hours, and concentrated in vacuo. The residual solid was washed with water, and purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent to give N-{4-{2-[4-(aminomethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (32.1 mg) as a pale yellow amorphous substance.
Reaction SMILES: BrBr.[CH2:3]([O:5][C:6]([CH:8]1[CH2:19][N:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]1=[O:27])=[O:7])[CH3:4].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[C:9](=[O:27])[C:10]2[CH:15]=[N:14][C:13]([S:16][CH3:17])=[N:12][C:11]=2[N:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)ncc2C1=O
Agent: BrBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(Cc2ccccc2)c2nc(SC)ncc2c1=O
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Bromine (0.68 g, 4.3 mmol) was added to a solution of 8-benzyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1.53 g, 4.28 mmol) in DCM (20 mL). After 30 minutes, the reaction mixture was concentrated. The residue was redissolved in DCM (20 mL) and triethylamine (1.08 g, 10.7 mmol) was added. After 15 h, water (10 mL) was added, the organic layer separated, dried (MgSO4), and concentrated. Chromatography on silica (0-50% EtOAc/hexanes gradient) provided 0.39 g 8-benzyl-2-methylsulfanyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.26 (s, 1H), 8.51 (s, 1H), 7.21-7.29 (m, 5H), 5.45 (s, 2H), 4.27 (q, 2H, J=7.1 Hz), 2.48 (s, 3H), 1.30 (t, 3H, J=7.1 Hz).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=3[CH:16]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)=[CH:16][C:15]=2[CH:17]=1
Reactant: CCOC(=O)N1CCC(c2cc3cc(Cl)ccc3o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: Clc1ccc2oc(C3CCNCC3)cc2c1

Procedure:
11.5 g of 4-(5-chloro-2-benzofuranyl)-1-piperidinecarboxlic acid ethyl ester is dissolved in 75 ml of ethylene glycol. After the addition of 50 ml of a 50% aqueous potassium hydroxide solution, the formed cloudy solution is heated, with vigorous stirring, for 15 hours at 160°; the reaction solution is thereupon cooled to 20°, and extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed five times with 1 liter of water each time, dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 300 ml of a 10% solution of methanesulphonic acid in water, and the acid solution extracted with ether. The aqueous solution is then adjusted by addition of 10% sodium hydroxide solution to have a pH value of 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 4-(5-chloro-2-benzofuranyl)-piperidine. The free base melts at 77°-78° after recrystallisation from hexane. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon it melts at 252°-254°.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:30]([O:34][C:35]([NH:37][C:38]1[C:39]([C:53](O)=[O:54])=[N:40][C:41]([C:45]2[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=2[F:52])=[C:42]([F:44])[CH:43]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:53]([C:39]3[C:38]([NH:37][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[CH:43][C:42]([F:44])=[C:41]([C:45]4[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=4[F:52])[N:40]=3)=[O:54])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)c(F)cc1NC(=O)OC(C)(C)C)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (13.0 mg, 0.032 mmol), 3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (14.2 mg, 0.039 mmol), HATU (30.5 mg, 0.080 mmol) in DMF (0.09 mL) and DIPEA (0.019 mL, 0.096 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (14.2 mg, 59%). LCMS calc. for C38H46F3N6O7 (M+H)+: m/z=755.3. Found: 755.1.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][F:33])[CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: FCCN1CCNCC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCN(CCF)CC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-(2-fluoroethyl)piperazine to afford an off-white powder. HPLC (Condition 4) tR=4.57 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=492.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.71 (m, 2H) 3.09-3.21 (m, 4H) 3.24-3.35 (m, 4H) 4.46 (t, J=4.89 Hz, 1H) 4.58 (t, J=4.89 Hz, 1H) 6.66 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.28-8.37 (m, 1H) 8.73 (d, J=1.95 Hz, 1H) 10.39 (br. s, 1H) 12.96-13.11 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[C:11]1([O:17][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)c1cccc(Cl)c1

Procedure:
Phenyl-3-chlorobenzoate is prepared by reacting 3-chlorobenzoyl chloride with phenol in toluene with some pyridine (1 mol equivalent per acid chloride) to trap the HCl that evolves. After aqueous extraction of the pyridinium salt and any excess starting materials, the product is crystallized from the toluene solution.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>O1CCCC1>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=3)[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccc([N+](=O)[O-])cc3)CC2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
0.91 g of 4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]-butylamine (2.64 mmol) and 0.53 g of triethylamine (5.28 mmol) were dissolved in 20 ml of tetrahydrofuran. 0.49 g of 4-nitro-benzoyl-chloride (2.64 mmol) were added at 0-5° C. After stirring for 2 h at 0-5° C., the solvent was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (2%). Fractions containing the product were combined. The solvent was evaporated to yield 0.51 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.[NH:40]1[C:44]([C:45]2[CH:46]=[C:47]([NH2:51])[CH:48]=[CH:49][CH:50]=2)=[N:43][N:42]=[N:41]1>C(Cl)Cl>[NH:43]1[C:44]([C:45]2[CH:46]=[C:47]([NH:51][C:29]([N:9]3[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:28])=[O:30])[CH:48]=[CH:49][CH:50]=2)=[N:40][N:41]=[N:42]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2cccc(-c3nnn[nH]3)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 41.4 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 90 mg, 0.90 mmol) in CH2Cl2 (2 mL) followed by reacting with 3-(1H-tetrazol-5-yl)-phenylamine (48.3 mg, 0.30 mmol) at rt for 30 min to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]amide (25.3 mg, 41.4%) as a white amorphous. HRMS (ES+) m/z Calcd for C30H27Cl2F2N7O+H [(M+H)+]: 610.1695. found: 610.1695
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][Cl:23]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][CH2:22][CH2:21][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCCCl)c2ccccc12
Temperature: 60 °C
Yield: 103.1 %

Procedure:
To a solution of 4-hydroxy-1-naphthaldehyde (8.6 g, 50 mmoles) and potassium carbonate (13.8 g, 100 mmoles) in N,N-dimethylformamide (DMF)(40 mL) was added 1-bromo-2-chloroethane (7.4 g, 50 mmoles). The mixture was heated at 60° C. overnight. The solution was diluted with ethyl acetate (500 mL), extracted with water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to obtain 12.1 g product (52% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1.Cl>CO.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:12]1([CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCCC1
Agent: Cl
Solvent: CO
Solvent: C1CCNC1
Solvent: O
Product: O=C1CC2(CCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15.8 g, 73.8 mmol), cyclopentanone (12.35 g, 147 mmol) and pyrrolidine (12 mL, 140 mmol) in MeOH (300 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromospiro[chroman-2,1′-cyclopentan]-4-one (23 g, 100%). 1H-NMR (CDCl3): 1.64 (m, 4H), 1.72 (m, 2H), 2.03 (m, 2H), 2.78 (s, 2H), 6.78 (m, 1H), 7.48 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.CC#N.O>CCCCO>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Solvent: O
Solvent: CC#N
Product: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Temperature: 155 °C
Yield: 74.1 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamide (215 mg, 0.590 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (414 mg, 2.07 mmol) were placed in n-BuOH (5 mL) and heated to 155° C. for 72 hours. The reaction was then cooled to room temperature and concentrated to dryness. The crude residue was purified by C-18 reverse phase flash chromatography (Biotage Horizon unit, C-18 25M column, 5-90% CH3CN/water gradient) to give (R)-tert-butyl 1-(5-bromo-3-(3-methoxybenzamido)-1H-pyrrolo [2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (238 mg, 74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].IC.[C:12](=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1Br
Temperature: 25 °C
Yield: 98.2 %

Procedure:
In a 250 mL r.b. flask, a solution of 2-bromo-4-chlorophenol (Lancaster: 16.94 g, 81.6 mmol, 1.0 equivuiv) in acetone (160 mL) was treated sequivuentially with iodomethane (6.10 mL, 98 mmol, 1.2 equivuiv), potassium carbonate (12 g), and water (4 mL). The reaction mixture was heated at reflux for 3 h, cooled to rt, and the bulk of the volatiles was removed under reduced pressure. The residue was poured into water (140 mL) and extracted with EtOAc (3×150 mL). The extracts were washed with brine (1×100 mL), combined, dried (K2CO3), filtered through a pad of Celite™, and concentrated to a clear oil. Short-path distillation (80-85° C., 1 Torr) afforded 17.74 g (98%) of 2-bromo-4-chloroanisole as a clear liquid. Data for 2-bromo-4-chloroanisole: 1H NMR (400 MHz, acetone-d6) 7.53 (d, J=2.5, 1H); 7.24 (dd, J=9.7, 2.5, 1H); 6.81 (d, J=9.7, 1H); 3.88 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[N:8](S(C)(=O)=O)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O>C1COCC1>[CH:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)n1c(C2CCCCC2)cc2cc([N+](=O)[O-])ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2[nH]c(C3CCCCC3)cc2c1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution containing 2-cyclohexyl-1-(methylsulfonyl)-5-nitro-1H-indole (5.8 g; 18 mmol) in THF (50 ml), tetrabutylammonium fluoride (1M solution in THF; 18 ml; 18 mmol) was added dropwise. The reaction mixture was refluxed for 18 hours, then cooled to room temperature. Water (50 ml) and EtOAc (50 ml) were added, the biphasic solution was transferred into a separating funnel, the organic layer separated and dried over Na2SO4, and the solvent was removed by evaporation under reduced pressure. The residue was purified by flash chromatography on silica gel (n-hexane/EtOAc, n-hexane 100→80%) to give 2-cyclohexyl-5-nitro-1H-indole (3.2 g), which was used without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:9]1[CH2:14][CH2:15][O:16][CH:8]1[C:7]1[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: OCCO
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1
Yield: 85 %

Procedure:
The mixture 5-methoxy-2-nitrobenzaldehyde (1 eq), ethylene glycol (1.4eq) and p-toluene sulfonic acid monohydrate (catalytic amount) in toluene was heated to reflux with a Dean-Stark apparatus for 16 hours. The mixture was then concentrated and passed through a plug of silica to give 2-(1,3-dioxolan-2-yl)-4-methoxy-1-nitrobenzene in 85-90% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:22]([C:29]1[O:33][C:32]([NH2:34])=[N:31][N:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:22]([C:29]1[O:33][C:32]([NH:34][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:10]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:2]=2[Cl:1])=[N:31][N:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1nnc(Cc2ccccc2)o1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)Nc2nnc(Cc3ccccc3)o2)c(Cl)c1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
90 mg (0.26 mmol) of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoic acid and 45 mg (0.26 mmol) of 5-benzyl-1,3,4-oxadiazol-2-amine are dissolved at room temperature (RT) in 8 ml of CH2Cl2. Then 248 mg (0.398 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.181 ml (1.3 mmol) of triethylamine, 6 mg (0.052 mmol) of 4-dimethylaminopyridine are added. Then the mixture is stirred at RT for 20 h and washed twice with 4 ml each time of water, dried over Na2SO4 and concentrated. The residue is purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 70 mg (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH:27]S(O)(=O)=O.C([O-])(O)=O.[Na+].[ClH:37]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:26])=[O:27])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:37]
Reactant: N#CCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reaction time: 6 h

Procedure:
An 18 mL-vial was charged with 2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetonitrile (12 mg, 0.033 mmol, synthesis of this compound was described in EXAMPLE 1). Concentrated H2SO4 (0.5 ml) was added at 0° C. The mixture was standing at room temperature for 6 hr. And then the mixture was added very slowly to NaHCO3 aq. at 0° C. The precipitate was collected and washed with water, dried. The product thus obtained was treated with 4N HCl in dioxane and the volatile material was removed under reduced pressure to give the desired product 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetamide as HCl salt (2.6 mg, 19% yield). MW=377.87. 1H NMR (CDCl3, 360 MHz) δ 7.83 (s, 1H), 7.69 (m, 1H), 7.18-7.30 (m, 7H), 5.77 (brs, 1H), 5.44 (brs, 2H), 3.58 (s, 2H), 3.08 (t, J=7.70 Hz, 2H), 2.83 (t, J=7.10 Hz, 2H), 2.21 (m, 2H).