Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([N:10]1[CH2:15][C@@H:14]2[C@@H:12]([CH2:13]2)[C@H:11]1[CH2:16][NH:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)=[O:9].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:7][C:5]1[S:6][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:36])=[C:3]([C:8]([N:10]2[CH2:15][C@@H:14]3[C@@H:12]([CH2:13]3)[C@H:11]2[CH2:16][NH:17][C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)=[O:9])[N:4]=1
Reactant: Cc1nc(C(=O)N2C[C@H]3C[C@H]3[C@H]2CNc2nc3ccccc3o2)c(Br)s1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2C[C@H]3C[C@H]3[C@H]2CNc2nc3ccccc3o2)c(-c2ccccc2C)s1
Temperature: 130 °C

Procedure:
To a solution of N-({(1R,2S,5S)-3-[(5-bromo-2-methyl-1,3-thiazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hex-2-yl}methyl)-1,3-benzoxazol-2-amine (0.010 g, 0.023 mmol) and 2-tolylboronic acid (0.012 g, 0.092 mmol) in DMF (0.25 mL) was added 1M aqueous cesium carbonate (0.092 mL, 0.092 mmol) and PdCl2(dppf) (0.0016 g, 0.0023 mmol) and heated in a microwave to 130° C. for 10 minutes. The system was cooled to room temperature, extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated. The crude reaction mixture was then purified using reverse phase conditions (5%→60% 0.1% TFA in water: 0.1% TFA in acetonitrile) followed by free basing with saturated sodium carbonate to afford the title compound (2-2) as a bone powder. 1H NMR (500 MHz, CDCl3) δ 7.35 (m, 1H), 7.19-7.34 (m, 5H), 7.14 (m, 1H), 7.02 (m, 1H), 4.29 (m, 1H), 3.98 (m, 1H), 3.52 (m, 2H), 3.39 (m, 1H), 2.75 (s, 3H), 2.32 (s, 3H), 1.81 (m, 1H), 1.44 (m, 1H), 0.882 (m, 1H), 0.548 (m, 1H). HRMS [M+H] C25H24N4O2S1 calc'd 445.1693, found 445.1679.
Reaction SMILES: N1CCCCC1.[CH2:7]([O:9][C:10](=[O:15])[CH2:11][C:12](O)=O)[CH3:8].[CH3:16][C:17]1[N:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:15])[CH:11]=[CH:12][C:20]1[CH:21]=[N:22][C:17]([CH3:16])=[CH:18][CH:19]=1)[CH3:8]
Reactant: Cc1ccc(C=O)cn1
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(C)nc1
Yield: 66.5 %

Procedure:
1.5 ml of piperidine are added to a solution of 25 g (0.19 mole) of malonic acid monoethyl ester in 50 ml of pyridine, followed by the dropwise addition of 17 g (0.14 mole) of 6-methyl-3-pyridine aldehyde. The mixture is refluxed for 5 hours and, after cooling, is poured onto a mixture of ice and concentrated hydrochloric acid. After extraction by shaking with diethyl ether, the organic phase is dried over sodium sulfate and concentrated by evaporation in vacuo, leaving 17.8 g (67%) of the title compound in the form of an oil which is further processed without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[Cl:14][CH2:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([F:11])[C:5]=1[F:10])[NH2:1]
Reactant: Nc1cc(F)c(F)c(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Nc1cc(F)c(F)c(CCl)c1
Reaction time: 2 h

Procedure:
To a stirring solution of (5-amino-2,3-difluorophenyl)methanol (4.13 g; 25.9 mmol) in DCM (78 mL) and NMP (11 mL) at RT was added dropwise thionylchloride (4.7 mL; 64.9 mmol). The mixture was allowed to react at RT overnight. Then, the mixture was poured into aqueous sodium bicarbonate solution/saturated aqueous sodium chloride solution/ice. The batch was stirred for 2 hours before it was extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated to give crude 3-(chloromethyl)-4,5-difluoroaniline.
Reaction SMILES: Cl.C([O:4][C:5](=[O:28])[CH:6]([CH2:23][S:24]C(=O)C)[CH2:7][C:8]1[C:9]([CH3:22])=[N:10][C:11]([NH:14]C(OC(C)(C)C)=O)=[CH:12][CH:13]=1)C>>[NH2:14][C:11]1[N:10]=[C:9]([CH3:22])[C:8]([CH2:7][CH:6]([CH2:23][SH:24])[C:5]([OH:28])=[O:4])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1C
Agent: Cl
Product: Cc1nc(N)ccc1CC(CS)C(=O)O
Yield: 90.7 %

Procedure:
Conc. hydrochloric acid (2 mL) was added to 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-yl)-propionic acid ethyl ester (77 mg, 0.19 mmol) under argon. The reaction was heated to reflux for 110 min and was then concentrated under reduced pressure to give the title compound (39 mg, 76%) as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:23][CH3:24])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1ccc(Cl)cc1C(=O)O
Product: COc1ccc(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-2-methoxybenzoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:5]=1)([O-])=O.O.C(Cl)Cl.[C:21](O)(=[O:23])[CH3:22]>[Fe]>[CH3:15][CH:14]([S:11]([CH2:10][C:6]1[CH:5]=[C:4]([NH:1][C:21](=[O:23])[CH3:22])[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12])[CH3:16]
Reactant: CC(=O)O
Reactant: CC(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cccc(CS(=O)(=O)C(C)C)c1
Temperature: 110 °C

Procedure:
A suspension of crude 1-nitro-3-[(propan-2-ylsulfonyl)methyl]benzene (5.0 g) in acetic acid (58 mL) was treated with iron powder (4.7 g), heated for 22 hours at 110° C. bath temperature and cooled to room temperature. Then water (250 mL) and DCM (250 mL) were added, stirred, filtered, dried with sodium sulfate and condensed. An analytical sample (200 mg) of the crude title compound (5.6 g) was recrystallized from diethyl ether/ethanol (121 mg). Lit.:[Grohmann and Hathaway, Molbank 2006, M502].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])([O-])=O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>O=[Pt]=O>[CH2:23]([O:22][C:19]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])=[O:21])[C:24]1[CH:6]=[CH:5][CH:4]=[CH:12][CH:11]=1
Reactant: CCOC(C)=O
Reactant: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Agent: O=[Pt]=O
Product: CN1CCC2(C)c3cc(NC(=O)OCc4ccccc4)ccc3N(C)C12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,2,3,3a,8,8a-Hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (2.2 g) was dissolved in ethyl acetate (100 ml) and hydrogenated in a Parr apparatus at 45 psi using PtO2 (220 mg) as a catalyst. The reduction was complete within 2 hours. The reduction was filtered directly into a nitrogen flushed flask. 4-Dimethylaminopyridine (0.100 g) and triethylamine (0.9 g) were added, the mixture was cooled to 0° C. and a solution of benzylchloroformate (1.5 g) in ethyl acetate (100 ml) was added over a period of 1.5 hours. The mixture was washed with water (2×100 ml), dried (Na2SO4), concentrated and purified by flash chromatography on silica gel (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 5-(benzoxycarbonylamino)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo-[2,3-b]indole (1.2 g).
Reaction SMILES: [IH:1].[CH3:2][NH:3][C:4](=[N:7][CH3:8])SC.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>C(O)C>[IH:1].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:4]([NH:7][CH3:8])=[N:3][CH3:2])=[CH:12][CH:11]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CN=C(NC)SC
Agent: I
Solvent: CCO
Product: CN=C(NC)NCc1ccc(C)cc1

Procedure:
A solution of N,N',S-trimethylisothiourea hydriodide, m.p. 208° -212° (9.84 g.) and p-methyl-benzylamine (4.84 g.) in ethanol (10 ml.) was refluxed for 31/2 hours, filtered, and refluxed for a further 21/2 hours. The solution was then concentrated, and the solid that separated was collected and crystallised from methanol-ethanol to give N-p-methylbenzyl-N', N"-dimethyl-guanidine hydriodide, m.p. 204° - 207°. Recrystallised from water, the m.p. rose to 209° - 212°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[O:24]1[C:28]2[C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:29]2[C:28]3[O:24][CH2:25][CH2:26][C:27]=3[CH:32]=[CH:31][CH:30]=2)=[O:34])=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,3-Dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=479.3.
Reaction SMILES: [C:1](=[NH:9])([O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[C:18]([N:9]=[C:1]([O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH3:5])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCCCC(=N)OCC
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=NC(=O)OCC)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A solution of 6.5 g (50.3 mmol) of ethyl valerimidate (free base) in 90 mL of dry CH2Cl2 was treated with 7.71 mL (5.60 g, 55.3 mmol) of triethylamine. The resulting solution was stirred under N2 at -10° C. in an ice salt bath as a solution of 4.81 mL (5.46 g, 50.3 mmol) of ethyl chloroformate in 10 mL of CH2Cl2 was added dropwise over 25 minutes. Upon completion of the addition, the cooling bath was removed, and the mixture was stirred at room temperature for 2 hours. Next, the solvent was removed by evaporation in vacuo. The residue was taken up in hexane and filtered to remove triethylamine hydrochloride. Concentration of the filtrate yielded 7.08 g (70%) of the product as a yellow oil, suitable for use in the next step without further purification. NMR indicated a mixture of syn and anti isomers. TLC (98:2 CH2Cl2 -MeOH) showed a close pair of spots, Rf 0.48, 0.52. 1H NMR (200 MHz, CDCl3, ppm): δ 0.86 (distorted t, J=7.5 Hz, 3H), 2.15-2.35 (m, 8H), 2.4- 2.65 (m, 2H), 2.19, 2.35 (t, J=7.5 Hz, 2H total), 4.0-4.2 (m, 4H). EI-MS: m/e 201 (M+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:23])[C:13]([N:15]([CH3:22])[N:16]=[C:17]([CH3:21])[CH2:18][S:19][CH3:20])=[O:14])[CH3:2].[OH:24]O>CO>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12](=[O:23])[C:13]([N:15]([CH3:22])[N:16]=[C:17]([CH3:21])[CH2:18][S:19]([CH3:20])=[O:24])=[O:14])[CH3:11]
Reactant: OO
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.2 %

Procedure:
To a 50 ml volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39) (5.60 g) and methanol (14 ml) were added, and cooled on ice-bath. 33% of aqueous hydrogen peroxide solution (2.1 g) was added dropwise thereto. Then, the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to chloroform) to give 1.95 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfinyl-2-propylidene)hydrazine ((4-19)-(1)-39).
Reaction SMILES: [OH:1][CH:2]([CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14](=S)[NH:15][N:16]=1.O.[NH2:24][NH2:25]>>[NH:24]([C:14]1[N:15]=[N:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]([OH:1])[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[CH:12][CH:13]=1)[NH2:25]
Reactant: NN
Reactant: CC(C)NCC(O)COc1ccccc1-c1ccc(=S)[nH]n1
Solvent: O
Product: CC(C)NCC(O)COc1ccccc1-c1ccc(NN)nn1

Procedure:
A stirred mixture of 6-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-3(2H)-pyridazinethione (1.5 g, 0.005 mole) and hydrazine hydrate (30 ml) was heated under reflux in an atmosphere of nitrogen for 90 minutes. Excess of hydrazine hydrate was removed under reduced pressure to give 3-hydrazino-6-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-pyridazine as an oil which was converted into an amorphous citrate (2 g, 83%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CCCCCCN1CCC(CN)CC1
Product: CCCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 51.4 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-hexylpiperidine (0.396 g, 2.0 mmol) according to procedure used for Example 2 to give 0.225 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH:18]=2)[C:13]([OH:15])=O)=[N:7][CH:8]=1)#[N:2].[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:13](=[O:15])[C:12]2[CH:11]=[C:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH:16]=2)[CH2:39][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cn3)cc(C(=O)O)c2)nc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cn3)cc(Oc3ccc(C#N)cn3)c2)CC1

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoic acid 0.35 g (0.97 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g, 0.97 mmol) were used to afford 0.4 g. of the required product. 1H NMR (DMSO-d6): δ 1.47 (9H, s), 1.72 (5H, m), 1.82 (3H, m), 3.20 (1H, m), 3.72 (1H, m), 6.74 (1H, m), 7.18 (1H, d), 7.32 (1H, s), 7.50 (1H, brs), 7.59 (1H, s), 8.08 (1H, brs), 8.30 (2H, dd), 8.39 (1H, dd), 8.67 (2H, d).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[C:12]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH:26](Br)[CH2:27][CH2:28]Cl)=[O:25])=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[N:1]1([C:26]2([C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:19][CH:20]=3)=[O:25])[CH2:28][CH2:27]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)C(Br)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccc(-c2ccccc2)cc1)C1(n2cncn2)CC1
Temperature: 0 °C

Procedure:
44.7 g (0.648 mol) of 1,2,4-triazole and 89.5 g (0.648 mol) of anhydrous potassium carbonate were suspended in 525 ml of acetonitrile, and, under reflux, 202 g (0.6 mol) of of acetonitrile, and, under reflux, 202 g (0.6 mol) of 1-bromo-3-chloropropyl 4-phenylphenyl ketone were added in portions over 20 minutes. After a reaction time of 3 hours under reflux, the mixture was poured into ice water and the crystals obtained were filtered off under suction. 162.0 g (93% of theory) of colorless crystals of melting point 154°-5° C. were obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:41]=[CH:40][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:39])[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[C:16]([CH3:28])=[C:17]([C:19]([N:21](C(=O)C(C)C)[NH2:22])=O)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:39])[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[C:16]([CH3:28])=[C:17]([C:19]3[O:12][C:11]([CH:13]([CH3:14])[CH3:18])=[N:22][N:21]=3)[CH:18]=2)=[O:12])=[CH:40][CH:41]=1)(=[O:4])=[O:3]
Reactant: Cc1c(C(=O)N(N)C(=O)C(C)C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Cc1c(-c2nnc(C(C)C)o2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
The compound obtained in step (b) (0.02 g, 0.034 mmol) in TMS-polyphosphate (3 ml, PPSE in DCM, Synthesis 1982, page 591-592) was stirred in a sealed vial and heated at 70° C. for 3 h. LC-MS showed complete conversion of the linear starting material to a compound with the expected MW. The cooled solution was diluted with DCM (10 ml) and was washed with water (10 ml). The organic phase was collected and the aqueous phase was extracted with another portion of DCM (10 ml). The combined organic phase was washed with brine and was then dried with Na2SO4. Filtration and evaporation of the solution gave a white solid. Purification of this material by preparative HPLC provided pure fractions which were freeze-dried. The title compound was obtained as a white solid (0.015 g, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][C:7]3([C:16]42[NH:20][C:19](=S)[C:18]([CH3:22])=[N:17]4)[CH2:12][CH2:11][CH:10]([CH:13]([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:25]>>[Br:1][C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][C:7]3([C:16]42[N:20]=[C:19]([NH2:25])[C:18]([CH3:22])=[N:17]4)[CH2:12][CH2:11][CH:10]([CH:13]([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(C(F)F)CC1
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(C(F)F)CC1
Temperature: 110 °C
Yield: 41.5 %

Procedure:
6′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 128 Step 3, 0.3 g, 0.73 mmol) was taken up in ammonia (7 M in MeOH) (6.22 mL, 43.6 mmol) and the resulting mixture was heated in the microwave reactor at 110° C. for 30 min. The solvent was evaporated. The same amount of ammonia was added and the mixture was heated and concentrated (5 times). The crude material was dissolved in EtOAc. Aq. citric acid solution (0.1 M) was added and the phases were separated. The citric acid phase was basified with 1 M NaOH and extracted with DCM twice. The combined DCM extracts were concentrated to give the title compound (0.120 g, 42% yield). 20 mg of the product was purified by preparative chromatography to give 11 mg of the title compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19-1.31 (m, 3 H), 1.34-1.48 (m, 3 H), 1.66-1.82 (m, 2 H), 1.90 (d, 1 H), 2.20 (s, 3 H), 2.80-2.95 (m, 2 H), 5.53-5.97 (m, 1 H), 6.53 (s, 2 H), 6.59 (s, 1 H), 7.21 (d, 1 H), 7.33 (d, 1 H); MS (ES+) m/z 396 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].N1(C2C=CC(C#N)=CC=2)CCNCC1.ClCC(Cl)=O.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:58])([F:57])[F:56])([O-:40])=[O:39]>>[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([O:54][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:56])([F:57])[F:58])([O-:40])=[O:39]
Reactant: N#Cc1ccc(N2CCN(C(=O)CCl)CC2)cc1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: N#Cc1ccc(N2CCNCC2)cc1
Agent: O=C(Cl)CCl
Product: N#Cc1ccc(N2CCN(C(=O)CO[C@H]3CC[C@H](Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1

Procedure:
4-(4-{2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetyl}-piperazin-1-yl)-benzonitrile was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-benzonitrile)-piperazine (also known as 4-[4-(2-chloroacetyl)-piperazin-1-yl]-benzonitrile) was prepared from 4-(piperazin-1-yl)-benzonitrile and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 4-(4-{2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetyl]-piperazin-1-yl)-benzonitrile was prepared from the 1-chloracetyl-4-(4-benzonitrile)-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (39% yield). The structure was confirmed using Protocol II-A. Calculated mass=532; observed mass=532; HPLC retention time=4.14 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Reaction time: 5 h

Procedure:
A vial (20 ml) equipped with a magnetic stirrer was charged with Raltegravir free (250 mg) and toluene (2.5 mL). A clear solution was obtained. KOH 30% (80 μL) was added at room temperature and the reaction was stirred for five hours. A solid precipitate formed and was separated by filtration. The product was dried in a vacuum oven at 45° C. for overnight to obtain Raltegravir potassium Form XIV.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([OH:36])[C:34]#[CH:35].[Al]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:35]#[C:34][CH2:33][OH:36])=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Product: O=C(c1ccc(C#CCO)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-iodophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Part A; 5.0 g, 9.0 mmol) was treated with propargyl alcohol (1.05 mL, 18.1 mmol) and Pd(PPh3)2Cl2 (190 mg, 0.27 mmol). The reaction vessel was covered with aluminum foil to keep out light, and CuI (35 mg, 0.18 mmol) was added. After stirring overnight at ambient temperature, the reaction mixture was filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (SiO2; 4% MeOH in CHCl3, saturated with NH4OH) gave 4.32 g (8.97 mmol; quantitative) of the title product as a light brown foam.