Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH:20]([C:22]1[N:23]=[CH:24][N:25]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=1)=[O:21]>>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:20]([C:22]1[N:23]=[CH:24][N:25]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:26]=1)[OH:21])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Yield: 73.2 %

Procedure:
In a similar manner to that described in Reference example 1, the reaction was carried out by using 6-bromo-2-tert-butyldimethylsilyloxynaphthalene (50.0 g) and 4-formyl-1-trityl-1H-imidazole (38.6 g) to give the titled compound (49.8 g) as a colorless powder.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH2:6])[CH2:4]O.[OH-].[Na+].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>COC(C)(C)C>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([N:6]2[CH2:4][C@H:3]2[CH2:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCC(N)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC[C@@H]1CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
R-(-)-2-amino-1-butanol (99.96 g, 105 mL) and tert-butyl methyl ether (TBME) (277 g, 366 mL) are combined under a nitrogen atmosphere. This mixture is stirred for several minutes and 10 N aqueous sodium hydroxide (449 mL) is added over a period of about 10 minutes. The reaction mixture is cooled to below 10° C. and a solution of p-toluene sulfonyl chloride (TsCl) (464 g) in TBME (711 g) is added over a period of about 50 minutes, maintaining the temperature of the reaction mixture at or below 32° C. After the addition is complete, the mixture is stirred for about 30 minutes at 40° C., and water (900 mL) is added while cooling the mixture to 25° C. The layers are separated and the organic layer washed sequentially with water (150 g) and 25% aqueous sodium chloride solution (300 g). Toluene (450 g) is added to the organic layer, and the mixture distilled under reduced pressure, maintaining the temperature of the mixture at or below 45° C., until the water content of the mixture is below about 0.1%. The resulting solution is used, without further treatment, for the preparation described in Example 2.
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:25]1([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([C:13]([C:12]3[C:7]([O:6][C:5]4[CH:28]=[C:29]([Cl:30])[C:2]([C:34]#[C:33][CH2:32][OH:35])=[CH:3][C:4]=4[Cl:31])=[N:8][CH:9]=[CH:10][CH:11]=3)=[O:14])[CH2:16][CH2:17]2)[CH2:27][CH2:26]1
Reactant: C#CCO
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Oc1cc(Cl)c(C#CCO)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 100 °C
Yield: 52.2 %

Procedure:
To a degassed suspension of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (100 mg, 0.19 mmol, 1.0 equiv; Example 163) in triethylamine (0.8 mL) under Ar was added 2-propyn-1-ol (216 mg, 220 μL, 3.85 mmol, 20 equiv; [CAS RN 107-19-7]), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol, 0.1 equiv; [CAS RN 14221-01-3]) and copper(I) iodide (3.7 mg, 0.02 mmol, 0.1 equiv; [CAS RN 7681-65-4]). The reaction mixture was heated by microwave irradiation to 100° C. for 1 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 49 mg (52%) of the title compound as an off-white powder. MS (ISP): 494.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[NH3:22]>>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1
Reactant: N#CCCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Product: N#CCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyronitrile (0.32 g.), saturated ethanolic ammonia (20 ml.) and yellow mercuric oxide (0.5 g.) was stirred at room temperature for 20 hours and then filtered and the filtrate evaporated to dryness. The residue was recrystallised from a mixture of acetone and petroleum ether (b.p. 60°-80°) to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyronitrile (0.29 g.), m.p. 137°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]=[N+:17]=[N-:18])[CH2:5][N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]([CH3:40])([CH3:39])/[CH:23]=[CH:24]/[C@H:25]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][CH:27]2[CH:33]([O:37][CH3:38])[C:34](=[O:36])[O:35][C@H:26]12>C(O)(C)C>[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C@H:6]1[CH2:5][N:4]([CH3:19])[C:3](=[O:20])[C@@H:2]([NH:1][C:34](=[O:36])[C@@H:33]([C@H:27]2[C@H:26]([OH:35])[C@@H:25](/[CH:24]=[CH:23]/[C:22]([CH3:39])([CH3:21])[CH3:40])[O:30][C:29]([CH3:32])([CH3:31])[O:28]2)[O:37][CH3:38])[CH2:8][CH2:7]1)=[N+:17]=[N-:18]
Reactant: CN1C[C@H](OCCCCCCN=[N+]=[N-])CC[C@H](N)C1=O
Reactant: COC1C(=O)O[C@H]2C1OC(C)(C)O[C@@H]2/C=C/C(C)(C)C
Solvent: CC(C)O
Product: CO[C@@H](C(=O)N[C@H]1CC[C@@H](OCCCCCCN=[N+]=[N-])CN(C)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Yield: 59.1 %

Procedure:
To a solution of (3S,6R)-3-amino-6-(6-azido-hexyloxy)-1-methyl-azepan-2-one (0.207 g, 0.73 mmol) in isopropanol (1 mL) is added (4R,4aR)-((E)-3,3-dimethyl-but-1-enyl)-7-methoxy-2,2-dimethyl-tetrahydro-furo[3,2-d][1,3]dioxin-6-one (0.3 g, 1 mmol) and heated to reflux for 18 h. The solution is evaporated under vacuum adsorbed on silica and chromatographed (CH2Cl2 to EtOAc gradient) to give 0.245 g (59%) of (R)-N-[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide as a solid. (ESI) 568.1 (M+H)+
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1)(O)=O.[CH3:20][NH:21][C:22](=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH2:25].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:20][N:21]1[C:22](=[O:30])[C:23]2[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:25]=[C:1]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:18][CH:19]=1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 25-28 (100 g., 0.36 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 12-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (95 g, Y=68%, P=98%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]([S:37]([NH:40][CH:41]2[CH2:43][CH2:42]2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[CH:41]1([NH:40][S:37]([C:33]2[CH:32]=[C:31]([NH:30][C:27]([C:26]3[CH:25]=[N:24][N:17]4[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]([C:6]5[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=5)=[N:15][C:16]=34)=[O:28])[CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH2:43][CH2:42]1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 612.2 [(M−H)−]; mp 225° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:21][N:20]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[O:21][N:20]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Alternatively, 2-Methyl-4-(trifluoromethyl)-1-({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indole-5-carbonitrile was synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1.O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: OCC1CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nnc2ccc(OCC3CC3)nn12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (2.64 ml) was initially charged in DMF (35 ml), admixed under argon with sodium hydride (795 mg) and stirred at 40° C. for 1 h. Subsequently, 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 1.66 g), dissolved in DMF (35 ml), were added dropwise. After 1 h, the mixture was admixed with water and extracted by shaking four times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated by rotary evaporation. The residue was triturated with MtB ether, filtered off with suction and dried. 720 mg of the title compound were obtained. LC-MS rt: 0.80 min [M+H]+: 206.1 (met. f)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)[N:15]=[CH:14][N:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[CH3:26][N:21]1[CH2:20][CH:19]=[C:18]([C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[CH:17]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C1=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CCNC1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN1CC=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1

Procedure:
This compound could be prepared from quinolin-7-yl-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-4-yl]-amine and formaldehyde in the presence of sodium triacetoxyborohydride and MeCN.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]2[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc2[nH]c(C)cc12
Reactant: ClCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1cc(C)n2Cc1cccc2ccccc12
Reaction time: 0.67 h
Yield: 97.1 %

Procedure:
4-Methoxy-2-methyl-1H-indole (644 mg, 4 mmol) was dissolved in 10 mL of DMF and 160 mg (4 mmol) of 60% NaH/mineral oil was added. After 0.67 hours, 707 mg (4 mmol) of 1-(chloromethyl)naphthalene was added. After 5 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 1.17 g (97% yield) of 4-methoxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.BrN1C(=[O:33])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH2:18][OH:33])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2CO)o1
Temperature: 70 °C
Reaction time: 4 h
Yield: 2.8 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.95 g, 5.56 mmol) in carbon tetrachloride (20 mL) was added N-bromo succinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70° C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) was added and stirring was continued for another 14 h at 70° C. N-Bromo succinimide (378 mg, 2.12 mmol) was added and the mixture stirred for another 4 h at 90° C. After the reaction mixture was cooled to 0° C. the suspension was filtered off and was washed with dichloromethane (30 mL l) and aqueous sodium hydrogencarbonate (1 N). It was extracted with dichloromethane and dried over sodium sulfate resulting in crude material (1.66 g). A part of this light brown solid (200 mg) was suspended in water (0.5 mL) and DMSO (2.0 mL) and the reaction mixture was stirred for 18 h at 60° C. the resulting solution was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate. Drying over sodium sulfate and urification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 20:60:20) afforded the title compound (57 mg, 33%) as a white solid. MS: m/e=368.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>ClCCl>[Si:11]([O:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:10])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: OCC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
To a cooled (0° C.) and stirred solution of 1-phenylethane-1,2-diol (1.0 g, 7.24 mmol) and tert-butyldimethylsilyl chloride (1.1 g, 7.24 mmol) in dichloromethane was added imidazole (0.74 g, 10.86 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 20 hours. The reaction mixture was washed with water, dried, and concentrated to yield 1.8 g of 2-(tert-butyldimethylsilanyloxy)-1-phenylethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([N:23]([CH2:21][CH3:22])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(=O)CC1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)N1C2CCC1CC(N1CCC(N(CC)c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(4-Oxo-piperidin-1-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester 2 (200.000 mg; 0.713 mmol; 1.000 eq.) was dissolved in DCE (4 mL) and treated with TEA (87.821 uL; 63.758 mg; 0.631 mmol; 1.000 eq.) and ethylaniline (91.79 mg; 0.856 mmol; 1.200 eq.), followed by NaBH(OAc)3 (453.569 mg; 2.140 mmol; 3.000 eq.) and AcOH (40.870 uL; 42.873 mg; 0.713 mmol; 1.000 eq.). The reaction was allowed to stir at room temperature for 48 hr and was quenched with MeOH (3 mL). The quenched mixture was allowed to stir at room temperature for 2 hrs, and the resulting suspension was filtered through a syringe filter. A 1 mL aliquot of the filtrate was purified by LC/MS (1 mL injection, 10-99 CH3CN gradient with 0.03% TFA, 15 minute run) to provide a pure sample of the desired product. LC/MS M/Z 372.2, retention time=1.82 minutes, 10-99% CH3CN/H2O gradient with 0.05% TFA.
Reaction SMILES: ClC1SC(C(O)[C:8]2[C:9](CC(C)C)=[C:10]([C:21]([O:23]C)=[O:22])[C:11](C(F)F)=[N:12][C:13]=2C(F)(F)F)=CN=1.C(N(CC)CC)C>[Pd].CO>[N:12]1[CH:13]=[CH:8][CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2cnc(Cl)s2)c1CC(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1cccnc1
Reaction time: 18 h

Procedure:
This example illustrates the preparation of Compounds 62, 106, 107, and 109, an example of reduction of a α-hydroxyhaloheterocyclomethyl derivative to the α-hydroxyheterocyclomethyl derivative, and oxidation of this derivative to compounds of the present invention. A mixture of methyl 5-[(2-chloro-5-thiazolyl)-hydroxymethyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (7.2 g, 16 mmol), 6 mL triethylamine, and 5% of palladium on activated carbon catalyst (5 g) in 80 mL methanol was placed in a Parr hydrogenation apparatus at 50 psi and RT for 18 h. The reaction mixture was filtered through celite. The celite was thoroughly washed with methanol. The combined filtrates was concentrated in vacuo. The residual solid was purified by flash chromatography on silica gel with 30% ethyl acetate-cyclohexane to afford 3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-(hydroxy-5-thiazolylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester (5 g, 73.5%) as A light yellow solid. m.p. 140°-150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:3][C:4]=2[F:25])=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4CCCC4=O)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (819 mg) described in Preparation Example 109 and pyrrolidin-2-one (0.16 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (49 mg) was obtained.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][CH3:34])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH2:33][CH3:34])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CCNC1CCCC1C(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(CC)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Ethylamino-cyclopentanecarboxylic acid ethyl ester (0.0926 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{ethyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C20H28N4O7S2 500.14, found 501.2 [M+H+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30]O.[NH2:33][C@@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30][NH:33][C@@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: OCc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example B191 step A, using [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methanol trifluoroacetate and tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate as the starting materials in 52% yield. LCMS for C28H34ClN6O2(M+H)+: m/z=521.3.