Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1.C(O)C.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:28][CH:29]=2)[N:14]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
tert-Butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I5) (0.250 g, 0.420 mmol) was dissolved in EtOAc (8 mL) and absolute ethanol (10 mL) under an atmosphere of nitrogen. 10% Pd/C (0.200 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (7×10 mL). The solvent was removed in vacuo to give the title compound (I6) (0.211 g, 84% yield) as a yellow solid. LCMS Method C: rt 6.78 min; m/z 600.3 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].Cl>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 511.4 [(M+H)+]; mp 251° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:23])[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(O)cc21
Reactant: O=S(CCCCBr)c1ccccc1
Product: CC1(C)OC(=O)Nc2c(Cl)cc(OCCCCS(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 4 from 8-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenylsulfinyl-butylbromide.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3]1.O[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=[CH:31][C:24]=2[S:23]1(=[O:36])=[O:35]>O>[O:35]=[S:23]1(=[O:36])[C:24]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][C:25]=2[C:26](=[O:27])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[O:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: CCOc1ccc2c(c1)C(=O)N(CCCCO)S2(=O)=O
Reactant: O=c1oc2ccccc2n1C1CCNCC1
Solvent: O
Product: CCOc1ccc2c(c1)C(=O)N(CCCCN1CCC(n3c(=O)oc4ccccc43)CC1)S2(=O)=O

Procedure:
From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)-1,1-dioxido-5-ethoxy-1,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: 1H NMR (400 MHz, CDCl3) 7.79 (d, J=8.57 Hz, 1H), 7.44 (s, 1H), 7.29-7.26 (m, 2H), 7.21 (d, J=6.89 Hz, 1H), 7.16-7.06 (m, 2H), 4.24-4.11 (m, 1H), 3.81 (t, J=7.3 Hz, 2H), 3.06 (br d, J=11.76 Hz, 2H), 2.45 (t, J=7.39 Hz, 2H), 2.36 (m, 2H), 2.11 (bt, J=11.08 Hz, 2H), 1.93-1.80 (br m, 6H), 1.65 (br m, 2H), 1.48 (t, J=6.97, 3H) Analysis calculated for C25H30N3O6S·HCl·1.2 H2O C: 53.75, H: 6.03, N: 7.52 found C: 53.72, H: 5.65 N: 7.52.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(N)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Yield: 84.2 %

Procedure:
A mixture of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-1 (2H)-pyridinecarboxylate (3.10 g, 11.3 mmol) and 10% Pd/C (1.00 g) in ethanol (100 mL) was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered through Celite and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane: methanol:isopropylamine 95:5:1) to give the desired product (2.63 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.10 (t, 1H, J=7.6 Hz), 6.62 (d, 1H, J=8.4 Hz), 6.60-6.59 (m, 2H), 4.27-4.18 (m, 2H), 3.62-3.58 (m, 2H), 2.80-2.72 (m, 2H), 2.62-2.59 (m, 1H), 1.89-1.52 (m, 4H), 1.49 (s, 9H); ESMS m/e: 277.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:19]([N+:16]([O-:18])=[O:17])[CH3:20]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=Cc1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture of 2,4-dichlorobenzaldehyde (1.45 g, 8.3 mmol), ammonium acetate (0.64 g, 8.3 mmol) and nitroethane (6 g, 80 mmol) was heated under reflux for 6 hr. The mixture was allowed to cool to room temperature and ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization from ethanol gave 2,4-dichloro-1-(2-nitro-1-propenyl)benzene (yellow needle crystals, yield; 1.0 g, 52%).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].CS(O[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20])(=O)=O.N1CCCN2CCCCCC=12>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][S:1][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]
Reactant: COC(=O)CS
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)CSCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
A mixture of methyl 2-mercaptoacetate (2.2 g), 2-bromophenethyl methanesulfonate (5.7 g), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (3.7 g) and THF (30 ml) was stirred at ambient temperature for 1.5 hrs and separation method A and E yielded the title compound (4.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.[Sn](Cl)Cl>CO.ClCCl>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](CSCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CSCc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
A mixture of (2R)-methyl-2-tert-butoxycarbonylamino-3-(4-nitro-benzylsulfanyl)-propionate (3.75 g, 10.1 mmol) and tin (II) chloride (5.76 g, 30.0 mmol) in methanol (50 mL) was stirred at 50° C. Upon completion (TLC: 5% methanol in dichloromethane), the mixture was cooled to room temperature, quenched with saturated potassium fluoride solution (75 mL) and extracted with diethyl ether (3×75 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography purification (SiO2; 1-2% methanol in dichloromethane as eluent) yielded the titled compound as an off-white solid. 1H NMR (CDCl3, 300 MHz) δ 7.08 (2H, d, J=8 Hz, ArH), 6.25 (2H, d, J=8 Hz, ArH), 4.53 (1H, m, CHN), 3.75 (3H, s, OCH3), 3.63 (2H, s, PhCH2S), 2.84 (2H, m, CH2CHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calculated for C16H24N2O4S 340.146, found 341 (M+H)+, 363 (M+Na)+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[O:11]=[C:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]1)[CH2:13][C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.[CH3:47][C:48]1[O:52][C:51]([C:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=2)=[N:50][N:49]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:47][C:48]1[O:52][C:51]([C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:14](=[O:15])[CH2:13][C:12](=[O:11])[N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[CH2:19][CH2:18]3)=[CH:55][CH:54]=2)=[N:50][N:49]=1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: Cc1nnc(-c2ccc(N)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(-c2ccc(NC(=O)CC(=O)N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)cc2)o1
Temperature: 10 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
HOBt (72 mg, 0.53 mmol) and DMAP (81 mg, 0.66 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (150 mg, 0.44 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (102 mg, 0.53 mmol) followed by 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenylamine (77 mg, 0.44 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using basic alumina (80% ethyl acetate in hexane) to afford 40 mg (20%) of N-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 502.17 (M+1)+, 94.56%, 1H NMR: (DMSO-d6): δ 10.5 (d, 1H), 7.92 (m, 2H), 7.8 (m, 4H), 7.68 (t, 1H), 7.56 (m, 1H), 3.68 (m, 7H), 3.44 (m, 2H), 3.18 (m, 1H), 3.08 (m, 1H), 2.58 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[C:16](=[CH:9]/[C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)/[C:17]#[N:18])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COc1ccc(C=O)cn1
Product: COc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cn1
Yield: 95.7 %

Procedure:
6-Methoxy-3-pyridinecarboxaldehyde (411 mg) was condensed with 3,4-dimethoxybenzyl cyanide (532 mg) through Method A (production step 2), to thereby yield the target product (yield: 850 mg, 96%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16]Br)=[O:5].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C1COCC1>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:5])[CH3:1]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Cl)cc(CN3CCOCC3)c2[nH]1
Temperature: 40 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 0.11 g (0.26 mmol) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in THF (1 ml) at RT, 40 μl of morpholine was added. The reaction mixture was stirred at 40° C. for one hour and concentrated under vacuo. The crude was dissolved in CH2Cl2 (1 m) and at RT, 0.2 ml of TFA was added and stirring was continued over night. Preparative HPLC (30% CH3CN/H2O) afforded 53 mg (62%) of 5-chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:11](=[O:12])[C:10]([CH3:15])([CH3:14])[CH3:9])[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccn1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73.6 %

Procedure:
This compound was prepared as reported by K. S. Gudmundsson et al, Synthetic Communications 1997, 27 (5), 861-870: To a stirred solution of 2-amino-4-chloropyridine (0.723 g, 5.62 mmol) in anhydrous pyridine (2.8 ml) was dropwise added trimethylacetyl chloride (1.02 g, 8.46 mmol). The reaction mixture was stirred at room temperature for 4.5 h under argon, then partitioned between ethyl acetate (70 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×30 ml), and the combined organics were washed with saturated aqueous NaHCO3 (40 ml), brine (50 ml), dried (Na2SO4), and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 50 g isolute silica column. Elution with 20% ethyl acetate in hexanes and 25% ethyl acetate in hexanes afforded the title compound as a white solid (0.880 g, 74%); 1H-NMR (250 Mz, DMSO-d6) 1.24 (s, 9H, C(CH3)3), 7.25 (dd, J=1.91 Hz, 5.36 Hz, 1H, 5-H), 8.17 (d, J=1.87 Hz, 1H, 3-H), 8.34 (d, J=5.35 Hz, 1H, 6-H), 10.09 (s, 1H, CONH); LC-MS (ESI, m/z) 6.91 min—213, 215 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][C:6]3=[CH:5][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[Br:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26]([NH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][C:6]3=[CH:5][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1cc1n2CCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1cc1n2CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A mixture of methyl 7-amino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 18, 0.300 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.427 g) in pyridine (4 mL) and DCM (12 mL) was stirred at room temperature for 30 minutes. The resultant mixture was diluted with ethyl acetate and washed with aqueous potassium carbonate solution (10%) and brine. The organic layer was dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-2% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.350 g) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[NH2:11][C:12]([NH2:14])=[NH:13].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:11][C:12]([NH2:14])=[N:13]2)=[CH:8][CH:9]=1
Reactant: N=C(N)N
Reactant: O=Cc1ccc(Br)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc2ccc(Br)cc2n1
Yield: 13.5 %

Procedure:
The 4-Bromo-2-fluoro-benzaldehyde (0.61 g, 3 mmol), guanidine (1.05 g, 5.83 mmol) and DMF were heated at 140° C. for 2.5 hours. 50 ml water was added to the mixture. The orange precipitate was filtered and washed with water. The solid was dissolved in 2N HCl. and filtered. The HCl solution was neutralized by ammonia hydroxyl. The off white solid was filtered and dried under vacuum to afforded the desired product (91 mg, 14%). MS (ESI) m/e 224 (M+1)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 7.00 (br. s., 2 H) 7.36 (d, J=8.82 Hz, 1 H) 7.77 (dd, J=9.16, 2.37 Hz, 1 H) 8.05 (d, J=2.37 Hz, 1 H) 9.09 (br. s., 1 H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C1C[O:23][CH2:22]C1>>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:22]=[O:23]
Reactant: C1CCOC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=Cc1ccncc1Br
Temperature: -60 °C
Yield: 76 %

Procedure:
A solution of di-isopropylamine (3.44 g, 34.1 mmol) was cooled to -78° C. and treated with n-butyl lithium 1.6M, 34.1 mmol). A solution of 3-bromopyridine (4.71 g, 30 mmol) in THF (5 ml) was added dropwise trying to keep the temperature below -70° C. The reaction was very exothermic, a solid precipitated and THF (2 ml) was added to improve stirring. The temperature rose to -45° C., after cooling to -60° C. and added remaining pyridine. DMF (2.49 g) in THF (15 ml) was added and the reaction stirred at -65° C. for 30 minutes. Water was added to quench the reaction and the reaction allowed to warm to ambient temperature. The reaction was partitioned between ethyl acetate/water and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated and the residue was subjected to chromatography (eluting with diethyl ether/hexane) to give 3-bromo-4-pyridinecarbaldehyde (1.4 g, 76%).
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[C:37]4[C@H:44]([CH3:45])[CH2:43][CH2:42][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:32][CH2:31]2)=[O:29])[CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])C(=O)OC(C)(C)C)=[CH:11][CH:10]=1>O1CCOCC1>[ClH:8].[ClH:1].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([CH2:16][NH:17][CH:25]([CH3:27])[CH3:26])[C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[C:37]4[C@H:44]([CH3:45])[CH2:43][CH2:42][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:32][CH2:31]2)=[O:29])=[CH:11][CH:10]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 189.5 %

Procedure:
4M HCl/dioxane (7.83 ml, 31.3 mmol) was added to a slightly cloudy solution of tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.679 g, 1.25 mmol) in dioxane (8 mL). The reaction mixture was stirred overnight under nitrogen (16 hours). The reaction mixture was concentrated to dryness and dried on a high vacuum line. The resulting residue was dissolved in minimal MeOH, and the solution was added dropwise to a stirring solution of ether, which caused a white precipitate to form. The resulting precipitate was isolated by filtration through a medium frit funnel with nitrogen pressure, rinsed with ether, dried with nitrogen pressure, dried in vacuo and then further in a 55° C. high vacuum oven for 2 days to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.610 g, 94.6% yield) as a white powder.
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[C:9]1([CH2:15][CH2:16][CH2:17][Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.Cl>C(OCC)C>[C:9]1([CH2:15][CH2:16][CH2:17][PH:4](=[O:3])[OH:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: CCOP(Cl)OCC
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=[PH](O)CCCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
Diethylchlorophosphite (15.7 g, 0.1 mol) in 50 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenylpropylmagnesium bromide (100 mL, 0.1 mol, 1.0 M solution of in Et2O) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and was stirred an additional 30 minutes. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. To the liquid was added 20 mL of water followed by 0.5 ml of concentrated hydrochloric acid. An exothermic reaction was observed and stirring continued for 20 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. To the clear liquid was added sodium hydroxide (40 mL, 2.0 M NaOH), the resulting solution stirred for 1 hour and then washed with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give 3-phenylpropylphosphinic acid (1, R=CH2CH2CH2Ph, R1=H) (9.8 g, 53%) as a clear and colorless oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][CH:21]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:21]1[CH:20]=[N:19][N:12]2[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=3)=[N:10][C:11]=12
Reactant: ClI
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3nccc3n2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of 5-(3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.0 g, 15.1 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.40 g, 17.1 mmol) and drop wise a solution of iodine monochloride (2.77 g, 17.1 mmol) in acetic acid (10 mL). The reaction mixture was stirred at room temperature for 16 h, diluted slowly with water (up to 100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 3-iodo-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (6.49 g, 94%) as a yellow solid. MS (EI) 457.0[(M)+]; mp 142° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[N:9]=1)([CH3:4])[CH3:3].[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1>ClCCl>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([NH:13][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)(=[O:34])=[O:33])[CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(N)c2F)n1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)n1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.204 mmol), 3-fluorobenzenesulfonyl chloride (40 mg, 0.204 mmol), and pyridine (0.162 mg, 2.04 mmol) were dissolved in dichloromethane (2 mL). After 2 h stirring, the reaction mixture was placed on silica gel and chromatography (0 to 30% EtOAc/Hexanes over 25 min.) to obtain N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide (83 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (s, 1H), 8.42 (d, J=5.49 Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.39-7.31 (m, 2H), 7.24 (t, J=7.87 Hz, 1H), 6.57 (d, J=5.31 Hz, 1H), 2.52 (s, 3H), 1.37 (s, 9H); MS (ESI); 499 (M−H)−.