Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>>[CH:21]([NH:25][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1)([CH2:23][CH3:24])[CH3:22]
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Reactant: CCC(C)N
Product: CCC(C)Nc1cc(Cl)cc2nc(NC(=O)c3cccnc3)nn12
Yield: 13.6 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and sec-butylamine (118 mg; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (15 mg, 13%). HPLC, Rt: 3.07 min. (purity 96.3%). LC/MS, M+(ESI): 344.8, M−(ESI): 342.9.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([NH:21][CH2:22]CNC(OC(C)(C)C)=O)[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OC)=O)=C(OS(C(F)(F)F)(=O)=O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.CN>C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([NH:21][CH3:22])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1NCCNC(=O)OC(C)(C)C
Agent: CN
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 122, starting from methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-(trifluoromethanesulphonyloxy)-benzoate (Intermediate 123) and 2M methylamine in THF.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:23][C:9]2[N:10]=[C:11]([NH2:22])[N:12]=[C:13]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:7]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:23][C:9]2[N:10]=[C:11]([NH2:22])[N:12]=[C:13]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C=Cc3ccccc3)nc(N)nc2s1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(CCc3ccccc3)nc(N)nc2s1
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-styryl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (78 mg, 0.18 mmol) in ethanol was added 5% palladium on activated charcoal (51 mg) which was stirred overnight under a hydrogen atmosphere. The suspension was filtered through celite, the volatiles removed in vacuo and the residue purified using semi-preparative HPLC to yield the pure compound as an orange powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:36][NH2:37])[CH:34]=2)[CH:29]=[CH:28]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:36][C:33]4[CH:34]=[C:35]5[C:30]([CH:29]=[CH:28][N:27]5[S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=5)(=[O:19])=[O:18])=[CH:31][CH:32]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CN)cc32)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cc32)cc1
Yield: 96.4 %

Procedure:
A microwave vial was charged with 53 (80 mg, 0.34 mmol), 36 (80 mg, 0.27 mmol), DIPEA (0.2 mL) and n-BuOH (2.0 mL), sealed and irradiated in a microwave reactor at 180° C. for 80 min. The reaction mixture was concentrated and purified with a CombiFlash® to afford 130 mg (95%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-indol-6-yl)methyl)pyrimidine-2,4-diamine (38) as yellow solid; MS (ESI) m/z=500.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=O.[C:14](#[N:17])[CH:15]=C.C(C(CCCC)CN(CC(CC)CCCC)CC(CC)CCCC)C>C1(=O)CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH:4]=[CH:15][C:14]#[N:17]
Reactant: C=CC#N
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Agent: CCCCC(CC)CN(CC(CC)CCCC)CC(CC)CCCC
Solvent: O=C1CCCC1
Product: Cc1ccc([N+](=O)[O-])cc1C=CC#N
Yield: 22.3 %

Procedure:
0.2877 g (0.5 millimol) of bis-(dibenzylideneacetone)-palladium(O), 9.98 g (50 millimols) of 2-methyl-5-nitrobenzoyl chloride, 3.31 g (62.5 millimols) of acrylonitrile and 17.68 g (50 millimols) of tris-(2-ethylhexyl)-amine, in 100 ml of cyclopentanone, are stirred for 1.5 hours at 100° C. The crude product is chromatographed on silica gel, in methylene chloride, and is then recrystallised from cyclohexane/carbon tetrachloride. 2.1 g (24% of theory) of 2-methyl-5-nitrocinnamonitrile are obtained in the form of white crystals; melting point 113.2° C.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9](C(OC(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][NH:9][C@H:8]([C:18]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: COCCN
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1CN[C@H](C(=O)NCCOC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, and 2-methoxyethylamine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=242.0.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[S:28](N)([NH2:31])(=[O:30])=[O:29]>O1CCOCC1>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][S:28]([NH2:31])(=[O:30])=[O:29])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: NS(N)(=O)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NS(N)(=O)=O)no2)cc1C#N
Temperature: 110 °C
Reaction time: 14 h
Yield: 25.8 %

Procedure:
Prepared using General Procedure 22: To a stirred solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (50 mg, 0.14 mmol) in dioxane (1.5 mL) was added sulfamide (66 mg, 0.69 mmol) and the mixture was heated to 110° C. After 14 h of stirring, the solvent was evaporated and the residue was purified by column chromatography. Additional purification by recrystallization from MeOH provided 15.9 mg (26%) of (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 248. LCMS-ESI (m/z) calculated for C21H21N5O4S: 439.5; found 440.1 [M+H]+, tR=3.42 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.08 (dd, J=16.1, 7.9 Hz, 1H), 4.80 (dt, J=12.1, 6.1 Hz, 1H), 4.65 (s, 1H), 4.59 (d, J=8.4 Hz, 1H), 3.50 (ddd, J=17.5, 8.8, 3.7 Hz, 1H), 3.30-3.09 (m, 1H), 2.87-2.67 (m, 1H), 2.07 (dt, J=21.3, 8.2 Hz, 1H), 1.47 (t, J=6.3 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([Cl:16])[CH3:10])=[CH:7][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc(C(F)(F)Cl)nc1
Solvent: ClCCl
Product: CC(Cl)c1ccc(C(F)(F)Cl)nc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of 1-{6-[chloro(difluoro)methyl]-pyridin-3-yl}ethanol (0.78 g, 3.77 mmol) in CH2Cl2 (40 mL) was added thionyl chloride (0.54 mL, 7.54 mmol) dropwise at room temperature. After 1 hr, the reaction was quenched slowly with saturated NaHCO3 aqueous solution and the two phases were separated. The organic layer was dried over Na2SO4, filtered, concentrated, and dried in vacuum to give 0.83 g of the crude 2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine (D) as brown oil in 98 percent yield, which was directly used for the next step reaction. GC-MS: mass calcd for C8H7Cl2F2N [M]+ 225. Found 225.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1>CCO.[Ni]>[CH3:1][C:2]1[C:3]([CH2:9][NH2:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c(C#N)n1
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc(C)c(CN)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
A solution of 3,6-dimethylpyridine-2-carbonitrile (264 mg, 2.00 mmol) in EtOH (10 mL) was treated with Raney-Ni (approximately 100 mg) and stirred under an atmosphere of hydrogen for 4 h at room temperature. The mixture was filtered through Celite and concentrated in vacuo to give the title compound (270 mg, 99%) as a yellow oil; NMR δH (400 MHz, CDCl3) 2.31 (3H, s), 2.51 (3H, s), 4.17 (2H, s), 7.00 (1H, d, J 7.5 Hz) and 7.37 (1H, d, J 7.5 Hz); M/Z 137 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C@:6]2([C@@H:11]([O:12][C:13]([CH3:15])=[O:14])[C@:10]3([OH:32])[CH2:16][C@@:17]45[S:29][S:28]SS[C@@:21]([CH2:30][OH:31])([N:22]([CH3:25])[C:23]4=[O:24])[C:19](=[O:20])[N:18]5[C@@H:9]3[CH2:8]2)[C:4](=[O:5])[C:3]1([CH3:34])[CH3:33].S(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:1][CH:2]1[O:7][C:6]2([CH:11]([O:12][C:13]([CH3:15])=[O:14])[C:10]3([OH:32])[CH2:16][C:17]45[S:29][S:28][C:21]([CH2:30][OH:31])([N:22]([CH3:25])[C:23]4=[O:24])[C:19](=[O:20])[N:18]5[CH:9]3[CH2:8]2)[C:4](=[O:5])[C:3]1([CH3:34])[CH3:33]
Reactant: CC(=O)O[C@H]1[C@]2(O)C[C@]34SSSS[C@](CO)(C(=O)N3[C@@H]2C[C@@]12OC(C)C(C)(C)C2=O)N(C)C4=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(=O)OC1C2(CC3N4C(=O)C5(CO)SSC4(CC31O)C(=O)N5C)OC(C)C(C)(C)C2=O
Reaction time: 0.25 h

Procedure:
Sirodesmin B (50 mg.) in dry pyridine (1.0 ml.) was treated with thionyl chloride (0.1 ml.) for 12 minutes at 0°C., then added to iced-water (25 ml.) and left for 15 minutes. The solution was adjusted to pH 2 with 2N.sulphuric acid, then extracted with chloroform (3 × 20 ml.). The extracts were dried over sodium sulphate, then concentrated to an oil (29.4 mg.) which was essentially Sirodesmin A but contained traces of Sirodesmin B and C. The crude product was purified by preparative t.l.c. on silica gel G.F. (solvent, formic acid: methanol: chloroform, 1:4:95) to yield Sirodesmin A as an oil (12.5 mg.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[OH-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]#[N:11]
Reactant: COc1ccccc1CC#N
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccccc1C(C#N)Cc1ccccn1

Procedure:
This intermediate (80 g.) was prepared using the procedure described in Example 14a except using 50 g. (0.339 mole) of (2-methoxyphenyl)acetonitrile, 56 g. (0.339 mole) of 2-(chloromethyl)pyridine hydrochloride, 60 g. (0.746 mole) of 50% aqueous sodium hydroxide, and 200 ml. of DMSO.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]([NH2:45])=[O:44])[CH2:39][CH2:38]1.[C:46]1([C:52]2([C:58]([OH:60])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(OCC)(=O)C>CO.ClCCl>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]([NH2:45])=[O:44])[CH2:39][CH2:38]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:55]3[CH2:54][CH2:53][C:52]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:58]([OH:60])=[O:59])[CH2:57][CH2:56]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: CN1CCN(C(N)=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid 4-methylpiperazine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with ethyl acetate, 3% methanol/dichloromethane, 6% methanol/dichloromethane, and then 10% methanol/dichloromethane, the title compound: Rf =0.41 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:26]([O:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](COC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A cooled solution of (R)-2-(tert-butoxycarbonylamino)-3-phenyl-1-propanol (92) (1 g, 4 mmol) in CH2Cl2 (20 ml) at 0° C. was treated with triethylamine (1.12 m, 8 mmol), pivaloyl chloride (0.74 ml, 6 mmol) followed by 4-(dimethylamino)pyridine (50 mg 0.4 mmol) and stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (1:4) as an eluant to give compound 94.
Reaction SMILES: [C:1](=[S:3])=S.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O(C(C)C)C(C)C>N1C=CC=CC=1>[N:24]([C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=3)[CH2:13][CH2:14]2)=[CH:23][CH:22]=1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1

Procedure:
To a stirred and cooled (ice-bath) mixture of 5 parts of N,N'-methanetetraylbis[cyclohexanamine], 25.2 parts of carbon disulfide and 40 parts of pyridine are added 6 parts of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine and the whole is stirred first for 1 hour in an ice-bath and further for 2 hours at room temperature. 35 Parts of 2,2'-oxybispropane are added and the whole is stirred for 30 minutes. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off again and recrystallized from 1,4-dioxane, yielding 2.45 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine; mp. 180.6° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:24]2[S:46][C:27]3=[N:28][C:29]([N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)=[CH:30][C:31](=[O:32])[N:26]3[N:25]=2)[CH:16]=[C:17]([C:19]([OH:23])(C)[CH2:20]O)[CH:18]=1)=[O:11])=O)(C)(C)C.O>C1COCC1>[C:19]([C:17]1[CH:18]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][NH2:8])[CH:14]=[C:15]([C:24]2[S:46][C:27]3=[N:28][C:29]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:30][C:31](=[O:32])[N:26]3[N:25]=2)[CH:16]=1)(=[O:23])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)cc(C(C)(O)CO)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(NC(=O)CN)cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(2-(3-(2-(tert-butoxycarbonylamino)-acetamido)-5-(1,2-dihydroxypropan-2-yl)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (27.0 mg, 0.041 mmol) in THF (0.5 ml)/Water (0.500 ml) is added NaIO4 (17.5 mg, 0.082 mmol). The mixture is stirred at room temperature for 2 h and then extracted with EtOAc (2×10 ml). The combined organic layers are washed with brine and dried over Na2SO4. After the removal of organic solvent in vacuo, the crude product (26 mg) is directly used without further purification for the next step as described in Step 6 of Example 1.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[CH:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]4C[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:25])[NH:4][CH2:3]1.[OH:26][C@@H]1CCNC1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[OH:26][C@@H:21]1[CH2:22][CH2:23][N:19]([CH2:18][CH2:17][CH2:16][O:15][C:11]2[CH:10]=[CH:9][C:8]3[N:7]4[C@H:2]([CH3:1])[CH2:3][NH:4][C:5](=[O:25])[C:6]4=[CH:14][C:13]=3[CH:12]=2)[CH2:20]1
Reactant: C[C@@H]1CNC(=O)c2cc3cc(OCCCN4CCCCC4)ccc3n21
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: C[C@@H]1CNC(=O)c2cc3cc(OCCCN4CC[C@@H](O)C4)ccc3n21
Yield: 39 %

Procedure:
The title compound was synthesized in analogy to example 2 from (R)-8-(3-chloro-propoxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 9, intermediate), (R)-3-hydroxy-pyrrolidine (commercially available), potassium carbonate and potassium iodide, to give the desired product as a light brown foam (39%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:13]=1[CH:14]=O.[NH4+].[Cl-]>C1COCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:13]=1[CH:14]=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=Cc1cc(I)ccc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cc1cc(I)ccc1Cl
Temperature: -78 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
Ph3PMeBr (9.10 g, 25.47 mmol) was added to anhydrous THF (34 mL) under N2 and then cooled to −78° C. KHMDS (1 M solution, 25.47 mL, 25.47 mmol) was slowly added to the solution and the resultant solution was stirred at −78° C. for 1 h. 2-chloro-5-iodobenzaldehyde (4.86 g, 22.14 mmol) in THF (10 mL) was then slowly added and the resultant solution allowed to warm slowly to room temperature overnight. After 16 h, saturated aqueous NH4Cl was added and the crude product extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4), concentrated, and purified by Biotage chromatography (0%-20% EtOAc/hexanes) to afford 4.32 g of product as an oil that solidifies (90%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.87 (d, J=2.27 Hz, 1 H) 7.50 (dd, J=8.34, 2.27 Hz, 1 H) 7.09 (d, J=8.34 Hz, 1 H) 6.99 (dd, J=17.56, 10.99 Hz, 1 H) 5.74 (d, J=17.43 Hz, 1 H) 5.43 (d, J=11.12 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1>Cl.[Fe].CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:24][CH3:25]
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1N
Yield: 76.3 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-28 by using 3-(2-chloro-6-fluorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one (0.100 g), iron powder (catalytic), conc. HCl (5-6 drops) and methanol (5 mL) to afford 0.070 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.77 (s, 3H), 4.81 (s, 2H), 6.66 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 7.50-7.57 (m, 2H), 7.68 (m, 1H), 12.39 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:21][NH:22][O:23][CH3:24].O>ClCCl>[CH:1]1([CH2:4][C:5]([N:22]([O:23][CH3:24])[CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: CNOC
Reactant: O=C(O)CC1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Stir cyclopropaneacetic acid (30 g, 300 mmol) in dichloromethane (1 L) and treat with 1,1′-carbonyldiimidazole (52.5 g, 324 mmol) slowly. Stir for 2 hrs at room temperature and treat with N,O-dimethylhydroxylamine hydrochloride (30 g, 308 mmol), neat, in one portion; stir overnight. Pour mixture into water and extract twice with dichloromethane. Wash organic layers with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, dry with magnesium sulfate, filter, and evaporate to provide the title compound (38 g, 89%). 1H NMR (CDCl3) δ 3.66 (s, 3H), 3.18 (s, 3H), 2.35 (d, J=8.0 Hz, 2H), 1.08 (m, 1H), 0.54 (m, 2H), 0.16 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@H:29]([OH:31])[CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@H:29]([OH:31])[CH3:30])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
140 mg of (R)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 435 mg of (R)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 403 mg of (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 298 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.1 (M)+.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[O:17])[CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[CH3:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[C:12](=[O:17])[CH2:11]1
Reactant: Nc1ccc(I)cc1
Reactant: CN1CCCNC(=O)C1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCCN(c2ccc(N)cc2)C(=O)C1
Yield: 15.2 %

Procedure:
A mixture of 4-iodoaniline (70 mg, 0.32 mmol), 4-methyl-2-homopiperazinone (35 mg, 0.27 mmol), K3PO4 (135 mg, 0.64 mmol) and 1,2-trans-diaminocyclohexane (16 uL, 0.13 mmol) in dioxane (4 mL) was degassed with Ar before being charged with CuI (18 mg, 0.095 mmol). The mixture in a sealed tube was heated at 110 C overnight. The mixture was then purified by a silica gel prep-TLC using CH2Cl2/MeOH (95/5) as solvents to give the titled compound (9 mg). MS 220.5 (M+H).