Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[N:17]1[C:22](=[O:23])[C:21]3=[CH:24][S:25][CH:26]=[C:20]3[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]1=[O:34])=[CH:14][C:13]([C:35]([F:38])([F:37])[F:36])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:45][C:46]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:47]=1[CH2:48]Br.C(OCC)(=O)C>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[N:9]([CH2:48][C:47]2[CH:50]=[C:51]([F:54])[CH:52]=[CH:53][C:46]=2[F:45])[C:10]2[C:15]([C:16]=1[N:17]1[C:22](=[O:23])[C:21]3=[CH:24][S:25][CH:26]=[C:20]3[N:19]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C:18]1=[O:34])=[CH:14][C:13]([C:35]([F:36])([F:37])[F:38])=[CH:12][CH:11]=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1[nH]c2ccc(C(F)(F)F)cc2c1-n1c(=O)c2cscc2n(C(=O)OC(C)(C)C)c1=O
Reactant: Fc1ccc(F)c(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1c(-n2c(=O)c3cscc3n(C(=O)OC(C)(C)C)c2=O)c2cc(C(F)(F)F)ccc2n1Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(1-tert-butoxycarbonyl-2,4-dioxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 51 (30 mg, 0.054 mmol) in anhydrous THF (1 mL) and anhydrous DMF (1 mL) was added potassium tert-butoxide (9 mg, 0.080 mmol) and 2,5-difluorobenzyl bromide 5J (14.6 mg, 0.071 mmol). The reaction mixture was stirred at room temperature for 3 hours. Ethyl acetate (50 mL) was added and the organic layer was washed with saturated ammonium chloride solution and brine. The organic layer was dried over sodium sulfate. The organic solvent was removed under reduced pressure to provide 3-(1-tert-butoxycarbonyl-2,4-dioxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-1-(2,5-difluorobenzyl)-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5K which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C@@:3]1([CH2:10][S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4]1)[CH3:2].Cl.[F:16][C:17]([F:34])([F:33])[CH2:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@:3]1([CH2:10][S:11]([N:28]2[CH2:29][CH2:30][CH:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:17]([F:16])([F:33])[F:34])=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)(=[O:13])=[O:12])[NH:4][C:5](=[O:9])[NH:6][C:7]1=[O:8])[CH3:2]
Reactant: CC[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: FC(F)(F)COc1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)F)cc3)CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
[(4S)-4-ethyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (WO 2004/024698) (869 mg) was added to a stirred solution of 4-[4-(2,2,2-trifluoroethoxy)phenoxy]piperidine hydrochloride (750 mg) and triethylamine (1.68 ml) in dichloromethane (50 ml) and the reaction stirred at ambient temperature for 2 hours. The solvents were removed in vacuo and the residue stirred in water for 2 hours. The resulting solid was filtered off, washed with water then ether and dried to give the title compound (1.13 g); NMR Spectrum: (DMSOd6) 0.78 (t, 3H), 1.25 (m, 2H), 1.66 (m, 4H), 1.94 (m, 2H), 3.11 (m, 2H), 3.49 (d, 1H), 3.58 (m, 1H), 4.41 (m, 1H), 4.64 (q, 2H), 6.97 (m, 4H), 8.5 (s, 1H), 10.71 (s, 1H); Mass Spectrum: M−H− 478.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18](Br)=[CH:17][CH:16]=3)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]1([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][C:22]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:24][CH:23]=4)[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2cc3cc(Br)ccc3cc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3cc4ccccc4cc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.5 %

Procedure:
Under an argon atmosphere, 29.0 g of phenylboronic acid, 25.7 g of 2,6-dibromoanthracene, 4.62 g of tetrakis(triphenylphosphine) palladium(0), 800 mL of toluene, and 400 mL of a 2-M aqueous solution of sodium carbonate were loaded, and then the mixture was stirred for 8 hours under ref lux. After the mixture had been cooled to room temperature, the precipitated crystal was taken by filtration. The resultant solid was repeatedly recrystallized with toluene and hexane and washed. Thus, 25.0 g of 2-phenylanthracene were obtained (in 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[N:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH:7]=O.[CH3:27][C:28]([S:31]([NH2:33])=[O:32])([CH3:30])[CH3:29].O.[BH4-].[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[N:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH2:7][NH:33][S:31]([C:28]([CH3:30])([CH3:29])[CH3:27])=[O:32]
Reactant: CC(C)(C)S(N)=O
Reactant: COC(=O)C(CCC=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CCCNS(=O)C(C)(C)C)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of 2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-5-oxo-pentanoic acid methyl ester 44a (0.066 g, 0.189 mmol) in THF (2 mL) at room temperature under Ar atmosphere was added 2-methyl-propane-2-sulfinic acid amide (0.023 g, 0.189 mmol) and titanium ethoxide (20 wt % solution in ethanol, 2 mL). The reaction mixture was stirred overnight at room temperature. Water (40 mL) was added, and the aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo. The reaction mixture was redisolved in MeOH (2 mL) and sodium borohydride (0.014 mg, 0.378 mmol) was added at room temperature. The reaction mixture was stirred for 1 h at room temperature, then water (40 mL) was added, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to provide crude product.
Reaction SMILES: [S:1]([O:5][CH2:6][C@H:7]1[O:14][C@@H:11]([O:12][CH3:13])[C@H:10]([NH:15][C:16]([NH:18][CH3:19])=[O:17])[C@@H:9]([OH:20])[C@@H:8]1[OH:21])([CH3:4])(=[O:3])=[O:2].C(O)(=O)C.[N:26]([O-])=[O:27].[Na+]>O>[S:1]([O:5][CH2:6][C@H:7]1[O:14][C@@H:11]([O:12][CH3:13])[C@H:10]([NH:15][C:16]([N:18]([CH3:19])[N:26]=[O:27])=[O:17])[C@@H:9]([OH:20])[C@@H:8]1[OH:21])([CH3:4])(=[O:3])=[O:2]
Reactant: O=N[O-]
Reactant: CNC(=O)N[C@H]1[C@H](OC)O[C@H](COS(C)(=O)=O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CO[C@@H]1O[C@H](COS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H]1NC(=O)N(C)N=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Methyl 2-deoxy-6-O-mesyl-2-(N'-methylureido)-β-D-glucopyranoside (400 mg) of the formula ##STR36## was dissolved in 50 ml of water, and the resulting aqueous solution was adjusted to pH 3 by addition of 2 ml of acetic acid. The acidified aqueous solution was admixed with 120 mg of sodium nitrite and the mixture was agitated at ambient temperature overnight to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) to remove the sodium ion therefrom. The reaction mixture was then evaporated under a reduced pressure at a temperature below 25° C. The residue was crystallized from ethanol to give 350 mg of the titled compound. mp. 131°-132° C. (with decomposition). [α]D20 -14° (c 0.5, dimethylsulfoxide).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)=[CH:35][CH:34]=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH:39]([C:36]1[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=1)[C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: Fc1ccc(C(CCCCCBr)c2ccc(F)cc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1CCCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 56 %

Procedure:
4-(3,4,5-trimethoxy-benzyl)-piperazine-2-carboxylic acid ethyl ester (2.0 g, 5.91 mmol) was dissolved in dry benzene (30 ml) followed by addition of triehylamine (0.65 g, 6.5 mmol) and resulting solution stirred for 1 hr. 1-[6,6-bis-(4-fluoro-phenyl)-hexyl bromide(2.08 g, 5.91 mmol) in dry benzene (30 ml) was added dropwise. The resulting mixture was stirred under nitrogen at room temperature overnight. The mixture was washed twice with water (30 ml) and dried over MgSO4 and evaporated. The crude product was purified by column chromatography using hexane:ethyl acetate (3:1) to give the desired product in 56% yield
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>CS(C)=O.O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:2])[CH2:16][O:17]2)=[CH:11][CH:10]=1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by following general procedure 3. To a solution of trimethylsulfonium iodide (3.5 g, 17.15 mmol, 1.2 equiv.) in DMSO (30 mL) was added sodium hydride 50%-55% dispersion in oil (0.97 g, 22.2mmol, 1.5 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 1-(4-fluorophenyl) ethanone (2 g, 14.47 mmol, 1 equiv.) in DMSO (10 mL) was added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The progress of the reaction was checked by TLC and the reaction mixture was poured in 100 mL water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (2×150 mL), followed by brine. The organic layer was dried over sodium sulfate and evaporated to dryness to yield a brown oil (2.2 g). 1H NMR (d6-acetone) was consistent with the structure. Product Rf 0.8 (ethyl acetate: hexane 10:90)
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:28])[NH:16][C:17]([C:20]4[CH:21]=C([CH:25]=[CH:26][CH:27]=4)C#N)=[N:18]3)=[C:13]([CH2:29][CH3:30])[N:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C([O:35][C:36](=[O:38])[CH3:37])C>Cl>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:28])[NH:16][C:17]([C:20]4[CH:21]=[C:37]([CH:25]=[CH:26][CH:27]=4)[C:36]([OH:35])=[O:38])=[N:18]3)=[C:13]([CH2:29][CH3:30])[N:12]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(C#N)c3)[nH]c(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(C(=O)O)c3)[nH]c(=O)c12
Temperature: 95 °C
Reaction time: 3 h

Procedure:
108 mg (0.27 mmol) cis-3-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl]benzonitrile (Example 40A) are dissolved in concentrated hydrochloric acid, and the reaction mixture is stirred at 95° C. for three hours. Sodium hydroxide (10% aqueous solution) (until a pH of 6–7 is achieved) and ethylacetate are added. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The product is purified by column chromatography.
Reaction SMILES: [N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+]>CC(O)C.CCOC(C)=O>[N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15](=[N:18][OH:19])[NH2:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: NO
Reactant: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: [N-]=[N+]=NC1COc2cc(C(N)=NO)ccc2C1O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Racemic (3R*,4S*)-3-azido-4-hydroxychroman-7-carbonitrile Int-2-C (5.08 g, 23.5 mmol) and hydroxylamine hydrochloride (3.27 g, 47.0 mmol) were mixed in 2-propanol (94.0 mL). To this suspension was added sodium bicarbonate (7.90 g, 94.0 mmol) and the resulting mixture was heated at reflux for 2 h. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc (250 mL) and washed with water and brine. The combined aqueous layers were extracted again with EtOAc. The combined organic layers were dried (MgSO4) and concentrated to afford racemic (3R*,4S*,E/Z)-3-azido-N′,4-dihydroxychroman-7-carboximidamide Int-2-D (5.71 g, 22.9 mmol, 97.5% yield): LCMS=250.08 [M+H]+.
Reaction SMILES: C(O)C.C([O:6][C:7](=O)[CH2:8][CH2:9][N:10]([C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=1)[CH:11]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12]1)C>C(O)(=O)C>[Cl:24][C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:7](=[O:6])[CH2:8][CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12]3)[C:17]=2[N:18]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCC(C)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CCC(N2CCC(=O)Nc3cnc(Cl)nc32)C1
Yield: 80.6 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 2.6 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(3-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-58) prepared in the previous step was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, and then water and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure to the crude product. Trituration of the residue with ether, provided 1.8 g of (rac)-2-chloro-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-58).
Reaction SMILES: N([O-])=O.[Na+].N[C@H:6]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7]([OH:9])=[O:8].[Br-:17].[K+].S(=O)(=O)(O)O>O>[Br:17][C@H:6]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7]([OH:9])=[O:8]
Reactant: [Br-]
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)[C@H](Br)CC1CCCCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 27.4 %

Procedure:
A solution of sodium nitrite (0.45 g, 6.5 mmol) in water (1.2 ml) was added dropwise at 0° C. over 4 hours to a stirred mixture of (R)-α-aminocyclohexanepropionic acid (1 g, 5.8 mmol), potassium bromide (2.3 g, 19.2 mmol) and concentrated sulphuric acid (0.66 ml) in water (7 ml). The mixture was stirred for 5 hours at 0° C. then at ambient temperature for 16 hours. The product was extracted into diethyl ether (4×20 ml) then the combined ethereal layers were washed with saturated aqueous sodium chloride solution (2×50 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by chromatography over silica gel eluting with a gradient of methanol: dichloromethane 1:50→1:20. Appropriate fractions were combined and the solvents removed in vacuo to give (R)-α-bromocyclohexanepropionic acid as a pale yellow oil 0.374 g, (27%). TLC (single spot, Rf=0.45, 10% methanol in dichloromethane), HPLC-MS (single main peak with Rt=8.88 mins, 234.1/236.1 [M+H]+, 257.2/259.2 [M+Na]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C.C(#N)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cc(Cl)n2nccc2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc3ccnn23)CC1
Temperature: 100 °C

Procedure:
To the reaction flask, 5,7-dichloropyrazolo[1,5-a]pyrimidine (896 mg, 4.8 mmol) was added along with tert-butyl 4-aminopiperidine-1-carboxylate (954 mg, 4.8 mmol), triethylamine (664 μL, 4.8 mmol), and acetonitrile (16 mL). The reaction was heated at 100° C. for 12 hours then cooled to room temperature, diluted with water, filtered and washed with water. The product, tert-butyl 4-(5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate, was collected as a solid in quantitative yield and dried under vacuum overnight. LCMS (M+1=352)
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C@@H:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](=[O:35])[CH2:33]Br)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C@@H:12]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:33][C:32]([C:31]1[CH:36]=[CH:37][C:28]([Br:27])=[CH:29][CH:30]=1)=[O:35])=[O:19]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC1=C(C)C(=O)C([C@H](CCCCCC(=O)O)c2ccccc2)=C(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=C(C)C(=O)C([C@H](CCCCCC(=O)OCC(=O)c2ccc(Br)cc2)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.8 %

Procedure:
A mixture of (7R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (0.71 g, 2.0 mmoles), p-bromophenacylbromide (0.56 g, 2.0 mmoles), and potassium carbonate (0.30 g, 2.2 mmole) in acetone (15 ml) was stirred for 2.5 hours at room temperature. After the reaction was completed, the solvent was evaporated in a reduced pressure, the residue was taken up in the isopropylether. Working up in the usual manner gave the crude product, which was chromatographed on silica gel column with isopropylether to give p-bromophenacyl (7R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoate (1.09 g, 99%) as an oil.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[O:20][CH3:21].O>ClCCl>[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][CH3:3])=[O:16])=[CH:13][C:12]=1[O:20][CH3:21]
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)Cl)ccc1I
Agent: CN
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(I)c(OC)c1
Yield: 46 %

Procedure:
4-Iodo-3-methoxy-N-methylbenzamide. N,N-Dimethylformamide (0.1 mL) was added to a solution of 4-iodo-3-methoxybenzoic acid (2.0 g, 7.2 mmol) in sulfuryl dichloride (20 mL), and the mixture was heated to reflux for 2 h. The excess sulfuryl dichloride was removed under reduced pressure to give the crude product 4-iodo-3-methoxy-benzoyl chloride. To a solution of methyl amine (0.72 g, 10.8 mmol) and triethylamine (2.18 g, 21.6 mmol) in dichloromethane (20 mL) was added dropwise a solution of the above 4-iodo-3-methoxy-benzoyl chloride in dichloromethane (15 mL) at 0° C. After the reaction was completed, water was added, the organic layer was separated, dried over sodium sulfate evaporated to give the crude product, which was purified on silica gel column (eluting with 10-17% ethyl acetate in petroleum ether) to give 4-iodo-3-methoxy-N-methylbenzamide (0.92 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.92 (d, J=8.0 Hz, 1H), 7.42 (d, J=5.6 Hz, 1H), 7.31 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[NH:32][C:31]4[CH2:30][CH2:29][NH:28][CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[NH:32][C:31]4[CH2:30][CH2:29][N:28]([CH3:35])[CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(c1cc2c([nH]1)CCNC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CN1CCc2[nH]c(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Reaction time: 0.25 h
Yield: 129.3 %

Procedure:
In methylene chloride (4.5 ml), 2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (200 mg) was suspended, followed by the addition of triethylamine (125 μl), acetic acid (77.0 μl), formaldehyde (a 37% aqueous solution, 56.1 μl) and sodium triacetoxyborohydride (139 mg) at room temperature. The resulting mixture was stirred for 15 minutes. To the reaction mixture, a saturated aqueous solution (20 ml) of sodium bicarbonate and methylene chloride (10 ml) were added to separate the water layer. The resulting water layer was extracted with methylene chloride (2×10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (25 g of silica gel, methylene chloride:methanol 10:1→7:1). The resulting solid was dissolved in a 1N aqueous hydrochloride in ethanol. After concentration of the resulting solution, water was added to the concentrate and the mixture was concentrated again, whereby the title compound (133 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11](Cl)=[O:12])=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([CH2:29][NH:30][C:11]([C:10]2[N:2]([CH3:1])[N:3]=[C:4]3[C:9]=2[CH:8]=[CH:7][CH:6]=[CH:5]3)=[O:12])[CH2:27][CH2:28]1
Reactant: NCC1CCN(CCc2ccccc2F)CC1
Reactant: Cn1nc2ccccc2c1C(=O)Cl
Product: Cn1nc2ccccc2c1C(=O)NCC1CCN(CCc2ccccc2F)CC1

Procedure:
The compound was obtained according to the procedure described in Example 7e) using as reactants 2-methyl-2H-indazole-3-carbonyl chloride (Example 1b) (880 mg; 4.5 mmol) and 1-[2-(2-fluorophenyl)ethyl]-4-piperidine methanamine (Example 12a) (1.06 g; 4.5 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:27][CH2:26][CH2:25][CH:21]([C:22]([OH:24])=[O:23])[CH2:20]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([N:19]3[CH2:27][CH2:26][CH2:25][CH:21]([C:22]([OH:24])=[O:23])[CH2:20]3)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: O=C(O)C1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCCC(C(=O)O)C3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (106.5 mg; 0.35 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). Nipecotic acid (Emkachem)(42.8 mg; 0.33 mmol; 1 eq.) and triethylamine (97 μl; 0.70 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, filtrated, affording Compound (21) as a brown solid (31 mg; 23%). M− (ESI): 393; M+ (ESI): 395. HPLC (method A), Rt: 2.60 min (purity: 95.4%).