Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:23]#[C:24][CH2:25][OH:26])=[CH:17][C:16]=3[F:27])=[O:11])=[CH:4][CH:3]=1>C(Cl)Cl.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:17][C:16]=3[F:27])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Yield: 66 %

Procedure:
A suspension of the title compound of Example 53 (0.300 g) and 10% Pd/C (0.03 g) in 25 mL of 3:1 CH2Cl2 /MeOH is hydrogenated at atmospheric pressure overnight. The reaction is filtered through celite. The filtrate is condensed. The crude product is recrystallized from EtOAc/hexanes to yield 0.200 g of the desired product as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[N:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:52]2[CH:53]=[C:54]([CH2:58][CH:59]3[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]3)[CH:55]=[CH:56][CH:57]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[N:15]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([C:56]5[CH:57]=[CH:52][CH:53]=[C:54]([CH2:58][CH:59]6[CH2:60][CH2:61][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:63][CH2:64]6)[CH:55]=5)[CH:3]=4)=[O:13])[CH:19]=[CH:18][CH:17]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)n1
Temperature: 100 °C
Yield: 113.2 %

Procedure:
To N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (40.46 g, 62.2 mmol) in a 2 L 3-neck flask was added 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (24.96 g, 62.2 mmol) and 1,4-dioxane (700 mL). Then potassium carbonate (25.8 g, 187 mmol) and water (233 mL) were added followed by tetrakis(triphenylphosphine)palladium(0) (3.59 g, 3.11 mmol) and the mixture was then stirred at 100° C. under nitrogen with conventional heating. After 2 h the reaction was cooled and the mixture was partitioned between ethyl acetate and water and the aqueous layer extracted well with ethyl acetate. The combined organics were washed with water, brine, dried (MgSO4), filtered and evaporated to give 59.49 g (113%) of a brown foam. The crude product was purified on a 750 g Companion XL silica cartridge, eluting with 0-100% of {1% MeOH in ethyl acetate} in dichloromethane over 14 column volumes. This gave 25.38 g (48%) of a pale beige foam that the lab HPLC showed to be 97.23% pure with a retention time of 2.60 min. LC-MS m/z 845 (M+H)+, 3.02 min (ret time).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:13]=[C:14]([C:18]2[N:23]=[C:22]([CH3:24])[C:21]([C:25](Cl)=[O:26])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([NH2:41])[CH:36]=[CH:35]2)(=[O:31])=[O:30]>C1COCC1.N1C=CC=CC=1>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([NH:41][C:25]([C:21]1[C:22]([CH3:24])=[N:23][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=3)=[N:19][CH:20]=1)=[O:26])[CH:36]=[CH:35]2)(=[O:31])=[O:30]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(ccn2N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(S(C)(=O)=O)ccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
2.0 M of NaHMDS (sodium bis(trimethylsilyl)amide) in THF is added to a stirred solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (0.72 mmol) and 5-methanesulfonyl-indol-1-ylamine (0.72 mmol) and in anhydrous pyridine (10 mL) at rt. The reaction mixture is stirred at 90° C. overnight and then concentrated in vacuo. The residue is purified ny silica gel chromatography eluting with 1.5% MeOH in DCM to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methanesulfonyl-indol-1-yl)-amide (50 mg, 8%) as a solid. MS: 425 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.86 (s, 3H), 3.02 (s, 3H), 6.55 (s, H) 6.92 (d, H), 7.17-7.38 (m, 3H), 7.53 (m, H), 7.78 (s, H), 8.27 (d, H), 8.38 (d, H), 9.16 (s, H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([S:31]([N:34]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:35]4[S:36][CH:37]=[CH:38][N:39]=4)(=[O:33])=[O:32])=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[C:17]([OH:49])[CH:16]=1>CN(C=O)C.CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([S:31](=[O:32])(=[O:33])[N:34]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[C:17]([CH:16]=1)[O:49][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4O)nccc3c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1-c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of Cs2CO3 (0.281 g, 0.863 mmol), ethyl bromoacetate (0.048 ml, 0.431 mmol) and 1-(4-fluoro-2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (From Step 1 in Example 189; 0.15 g, 0.288 mmol) in DMF (2.88 ml) was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography (25 g column), eluting with EtOAc:Hex: 0-50% to obtain ethyl 2-(5-fluoro-2-(6-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetate as light yellow solid. m/z (ESI) 608.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[OH:10].C(=O)([O-])O.[Na+].[CH3:16][O:17][C:18](OC)([O:23]C)[C:19](OC)=O>>[OH:9][C:6]1[CH:7]=[CH:8][C:3]2[N:2]=[C:19]([C:18]([O:17][CH3:16])=[O:23])[O:10][C:4]=2[CH:5]=1
Reactant: COC(=O)C(OC)(OC)OC
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1nc2ccc(O)cc2o1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 4-aminobenzene-1,3-diol hydrochloride (i in Scheme 1) (0.50 g, 3.1 mmol) and sodium hydrogen carbonate (2.5 mg) in methyl trimethoxyacetate (2 mL) was stirred at 100° C. overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=9/1) to afford methyl 6-hydroxybenzo[d]oxazole-2-carboxylate as a white solid (0.49 g, 82%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.26 (s, 1H), 7.70 (m, 1H), 7.12 (m, 1H), 6.95 (m, 1H), 3.92 (s, 3H) ppm; MS (ESI): 194.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]([NH2:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]([N:20]2[CH2:29][CH2:28][CH:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:30][CH2:31]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(N)C1
Reactant: CCC(CC)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(N2CCC(c3ccccc3)CC2)C1

Procedure:
To a solution of amine (from Example 104, Step E) and (±) -1, 5-dibromo, 3-phenyl-pentane in 0.5 mL of isobutylnitrile was added 0.080 mL of DIEA and a catalytic amount of tetrabutyl-ammonium iodide. After warming the reaction to 95° C. for 22 h, the mixture was partitioned between 10 mL of CH2Cl2 and 10 mL 1N NaOH. After separating layers, the aqueous phase was extracted with 10 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography eluting with 10% EtOAc in hexanes to provide 10 mg of the title compound: 1H NMR (300 MHz, CDCl3): δ1.2-1.9 (m, 16H), 2.1-2.4 (m, 2H), 2.6-3.0 (m, 6H), 4.0-4.4 (m, 2H), 7.0-7.4 (m, 10H). RF : 0.45 (20% EtOAc in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[NH:11][C:10](=O)[N:9]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[N:11]=1
Reactant: O=c1nc(-c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2nc(Cl)nc(-c3ccccc3Cl)c2c1

Procedure:
A mixture of 40 g of 4-(2-chloro phenyl) 6-nitro 2-quinazolone are 600 ml of phosphorus oxychloride is heated to reflux for 4 hours. The phosphorus oxychloride is evaporated in vacuo to dryness, then the residue is poured into an ice-water mixture. It is rendered alkaline with a 10% sodium hydroxide solution. The precipitate is drained and washed with acetonitrile. The product is purified by chromatography over a column of silica. By eluting with a chloroform-methanol (95-5 vol/vol) mixture, the expected product is isolated. Weight: 27 g; m.p.: 228° C. (isopropanol).
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][O:2]2.CC1([O:17]C(=O)C)CCCC=C1>[Pd+2]>[CH:1]12[CH:9]([OH:17])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][O:2]2
Reactant: C1CC2CCOC(C1)C2
Reactant: CC(=O)OC1(C)C=CCCC1
Agent: [Pd+2]
Product: OC1C2CCCC1OCC2

Procedure:
When m is 0, n is 2 or p is 3, the ring system is a 2-oxabicyclo[3.3.1]nonane, another subclass of the invention. For example, a compound of subclass XVI of formula XVIp below ##STR30## in which R2, R5 and R6 are methyl in formula 1 can be prepared by treating 3-methyl-3-acetoxycyclohex-1-ene with a malonic ester in the presence of palladium(II), the resulting cyclohexene diester is hydrolyzed, decarboxylated, and treated with methyl Grignard reagent. The resulting cyclohexenylalkanol is epoxidized and cyclized to yield the 2-oxabicyclo[3.3.1]nonan-9-ol, which is treated with WCH2X in which X is halogen to yield the desired ether XVIp. Alternatively, 3-methyl-2-cyclohexen-1-carboxylic acid is converted to 3-methyl-2-cyclohexen-1-acetic acid by methods analogous to those of the literature and described for compounds of formula XIp, the resulting acid is treated with methyl Grignard, and the resulting alcohol is subjected to epoxidation-cyclization to yield 2-oxabicyclo[3.3.1]nonan-9-ol.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](=O)[C:25]1[O:29][CH:28]=[CH:27][CH:26]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:24]([C:25]3[O:29][CH:28]=[CH:27][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ccco1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: c1coc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in dimethylformamide (2 mL) was added furfural (80.7 mg, 0.840 mmol) and oxone (258 mg, 0.420 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (121 mg, 49% yield) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].CCN(C(C)C)C(C)C.[SH:24][CH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][CH2:25][S:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: OCCCS
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc2ccc(I)cc2c1SCCCO

Procedure:
Similar procedure as described in example 39a was used, starting from 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c), DIEA and 3-mercapto-1-propanol to give 4-(3-hydroxy-propylsulfanyl)-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 371 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=1>>[CH:14]1([CH2:13][N:12]2[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=[C:8]2[C:7]2[C:2]([O:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(CO)cc1
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Product: COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (Ex. 1, intermediate a) and (4-methoxy-phenyl)-methanol (CAS Reg. No. 105-13-5). Colorless solid (31%). MS (Turbo Spray): m/z=464.2 (M+H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:17]2[C:18]3[N:9]([C:10](=[O:30])[CH2:11][N:12]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[C:13]=3[CH:14]=[CH:15][C:16]2=[O:19])[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>C(#N)C>[CH3:48][C:46]([O:45][C:44]([NH:43][CH:40]1[CH2:39][CH2:38][N:37]([CH2:6][C@H:7]2[N:17]3[C:18]4[N:9]([C:10](=[O:30])[CH2:11][N:12]([C:20]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])[C:13]=4[CH:14]=[CH:15][C:16]3=[O:19])[CH2:8]2)[CH2:42][CH2:41]1)=[O:50])([CH3:47])[CH3:49]
Reactant: CS(=O)(=O)OC[C@@H]1CN2C(=O)CN(C(=O)OCc3ccccc3)c3ccc(=O)n1c32
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2CN3C(=O)CN(C(=O)OCc4ccccc4)c4ccc(=O)n2c43)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Phenylmethyl (1S)-1-{[(methylsulfonyl)oxy]methyl}-3,8-dioxo-1,2,3,4-tetrahydro-5H,8H-2a,5,8a-triazaacenaphthylene-5-carboxylate (232 mg, 0.508 mmol) was dissolved in dry acetonitrile (10 ml) at room temperature under argon and treated with pyridine (0.049 ml, 0.610 mmol). 1,1-Dimethylethyl 4-piperidinylcarbamate (127 mg, 0.610 mmol) was then added and the reaction was heated at 70° C. overnight. Then 0.049 ml of pyridine and 127 mg of 1,1-dimethylethyl 4-piperidinylcarbamate were added to the reaction and the temperature was increased to 80° C. for 8 h and then the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue partitioned between sat NaHCO3 and DCM (50/50 ml). The layers were separated and the aqueous layer was extracted with DCM again (2×50 ml). The combined organic extracts were dried (MgSO4) filtered and evaporated to afford 280 mg of crude product which was purified by silica chromatography using a 0-5% methanol/dichloromethane gradient to afford the product as a yellow gum (130 mg, 47.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14]O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][Br:40])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)cc(Sc2ccccc2CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(OC)cc(Sc2ccccc2CBr)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
2-(3,5-Dimethoxyphenylthio)benzyl alcohol (7.9 g) was dissolved in methylene chloride (40 ml), then triphenylphosphine (11.2 g) and carbon tetrabromide (11.2 g) were added thereto, the mixture was stirred at room temperature for ten minutes, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1) to give 2-(3,5-dimethoxyphenylthio)-benzyl bromide (9.53 g, yield of 98%).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(N)[nH]n1
Reaction time: 24 h
Yield: 96.5 %

Procedure:
600 mg (10%) palladium on carbon is added under inert atmosphere to 5.88 g (25.77 mmol) of tert-butyl 5-nitro-1H-pyrazol-3-ylcarbamate diluted in 145 ml of methanol and then the reaction mixture is stirred under hydrogen atmosphere for 24 hours. The solution is filtered on Celite and then rinsed with ethyl acetate. The filtrate is concentrated to yield 4.93 g (96%) of tert-butyl 5-amino-1H-pyrazol-3-ylcarbamate in the form of a gray solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-:12].[Na+].Cl>CS(C)=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 60 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 2,4-dichloro-1-nitrobenzene (100 g, 0.52 mol) in DMSO (200 mL), aqueous solution of NaOH (41.6 g, 1.04 mol) in water (42 mL) was added and the resulting mixture was stirred 60° C. for 16 h. The mixture was allowed to cool to room temperature, poured to ice water, and then acidified with aqueous HCl (1M) to adjusted the pH to 3-4. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was used directly in the next step (80 g, 88% yield).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:46]([C:69]([F:72])([F:71])[F:70])=[N:47][N:48]([C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([C:69]([F:70])([F:72])[F:71])=[N:47][N:48]([C:50]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:49]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-(trifluoromethyl)-1-trityl-1H-pyrazole and used in the consecutive step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=[N:13]2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:14]=[N:13]2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-n2cc(CCCc3ccccc3)nn2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of ethyl 4-methyl-2-(4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylate (7.04 g, 19.78 mmol) in a mixture of tetrahydrofuran (25 mL) and water (25 mL) was added lithium hydroxide (4.15 g, 98.90 mmol). The reaction mixture was stirred at ambient temperature 18 hours, acidified with 10% hydrochloric acid solution, and extracted with dichloromethane (2×100 μL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford the title compound in 89% yield (5.82 g): 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.31-7.15 (m, 5H), 2.75-2.49 (m, 7H), 2.00-1.95 (m, 2H); MS (ES+) m/z 329.2 (M+1).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[CH:20][CH:21]=3)[CH2:11][CH:10]([C:22]3[O:24][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[N:26]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=NO)c1ccccn1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccn4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyridine-2-carboximidamide were reacted according to the General Method 1. Yield: 27 mg (30% of theory)