Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([S:26]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N+:34]([O-])[CH:33]=[CH:32]3)(=[O:28])=[O:27])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[N:40]1C=CC=CC=1>>[NH2:40][C:35]1[C:36]2[C:31](=[CH:30][C:29]([S:26]([N:22]3[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]3)(=[O:28])=[O:27])=[CH:38][CH:37]=2)[CH:32]=[CH:33][N:34]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccc3c[n+]([O-])ccc3c2)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccc3c(N)nccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
310 mg of p-toluenesulfonyl chloride was added to a pyridine (20 mL) solution of 510 mg of 6-(4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl)isoquinoline 2-oxide obtained in Step 1 of Example 53, and the mixture was stirred at room temperature for 16 hours. Then, the reaction solvent was distilled off under reduced pressure. To the obtained residue, 9 mL of 2-ethanolamine was added, and the mixture was stirred at room temperature for 6 hours. After the completion of reaction, the reaction solution was poured into ice water, and the deposited white crystal was collected by filtration. The obtained crystal was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 380 mg of the compound of interest as a white crystal (75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][OH:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2].[CH3:46][C:47]1[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1.Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][O:43][S:53]([C:50]4[CH:51]=[CH:52][C:47]([CH3:46])=[CH:48][CH:49]=4)(=[O:55])=[O:54])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CCO)C(=O)OCC)CC2)c2ncnn12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CCOS(=O)(=O)c3ccc(C)cc3)C(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-hydroxybutanoate (0.47 g), 4-methylbenzenesulfonyl chloride (0.59 g) and pyridine (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 70%).
Reaction SMILES: Cl.O.[NH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[NH2:4].[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH:24][C:25](=[O:37])[C:26](=[CH:33]N(C)C)[C:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]2>CO>[CH:16]12[CH2:22][CH:20]3[CH2:19][CH:18]([CH2:23][CH:14]([CH2:21]3)[CH:15]1[NH:24][C:25]([C:26]1[CH:33]=[N:4][N:3]([C:5]3[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=3)[C:27]=1[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:17]2
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CN(C)C=C(C(=O)NC1C2CC3CC(C2)CC1C3)C(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
Hydrochloric acid (34.5% w/w, 15.88 g, 5.48 g @100.0%, 0.1504 mole, 1.0 mol. eq) and water (70 ml, 1.4 rel. vol) were added to a suspension of 4-hydrazinobenzoic acid (23.35 g, 22.88 g @100.0%, 0.1504 mole, 1.0 mol. eq) in methanol (1250 ml, 12.5 rel. vol). The resulting suspension was stirred for 30 min at 20 to 25° C. and a solution of N-(2-adamantyl)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanamide (intermediate #4) (53.47 g, 50.0 g @100.0%, 0.150 in 4 mole, 1.0 mol. eq) at 20-25° C. in methanol (250 ml, 5.0 rel. vol)] added over a period of 20 minutes followed by hydrochloric acid (34.5% w/w, 2.38 g, 0.82 g @100.0%, 0.02264 mole, 0.15 mol. eq) and water (70.0 ml, 1.4 rel. vol). The reaction mass temperature was increased to 62-65° C. and maintained for 90.0 min. For work up methanol solution was concentrated atmospherically until the residual volume 6.0 rel. vol (300.0 ml) remained. The resulting suspension was cooled to 20-25° C. and stirred for 1.0 hr. The product was filtered and washed with ethyl acetate (200.0 ml, 4.0 rel. vol) and sucked dry for 30 min. The product was dried under vacuum (100 mbar) at 50° C. for 8 hrs to give crude 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (47.0 g, 73.0%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O-:24])=[O:23])[CH2:18][CH:17]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C(OCC)(=O)C>[N:37]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:13]([CH3:16])([CH3:14])[CH3:12])=[O:23])[CH2:18][CH:17]3[O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:12][CH:11]=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCCOc1ccc(C2CCN(C(=O)[O-])CC2OCc2ccc3ccccc3c2)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCN3CCOCC3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
A solution of 200 mg (0.35 mmol) of tert-butyl 3RS,4RS)-4-[4-(3-methylsulphonyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 1 ml of ethyl acetate was treated with 60 μl of morpholine and boiled under reflux for 3 hours. Subsequently, the reaction solution was diluted with 5 ml of ethyl acetate and extracted twice with 1 ml of saturated sodium hydrogen carbonate solution each time. The organic phases were dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The colourless oil (169 mg) was chromatographed on silica gel using ethyl acetate and the eluent. There were obtained 142 mg of tert-butyl (3RS,4RS)-4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in the form of white crystals; MS: 561 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]5[CH:26]=[CH:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>O1CCCC1>[CH:31]([NH:34][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:27]([F:29])([F:28])[F:30])[CH:11]=2)=[O:22])=[CH:16][CH:17]=[C:18]2[C:19]=1[NH:24][CH:25]=[CH:26]2)=[O:23])([CH3:33])[CH3:32]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cc[nH]c3c12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
To a solution of 110 mg (0.25 mmol) of the crude 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1H-8-oxa-1,6-diaza-cyclopenta[a]naphthalen-9-one in 2.5 mL of anhydrous tetrahydrofuran, under Argon, is added 0.07 mL (0.77 mmol) of isopropylamine. The reaction is stirred during 5 hours at ambient temperature and then quenched with an aqueous saturated solution of ammonium chloride. The product is extracted twice with ethyl acetate and the combined organic phases are dried on Na2SO4, filtrated and the solvent is evaporated. After purification by flash chromatography on silica gel with hexanes and ethyl acetate as eluents and a preparative thin layer chromatography, 18.5 mg (0.04 mmol, 16%) of a white solid are obtained; LC/MS:513/515 (M+Na)+, m.p.: 240-242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](COC)[C:12]2[C:13]([C:19]([C:21]3[C:22]4[CH:29]=[N:28][NH:27][C:23]=4[N:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]4[CH:29]=[N:28][NH:27][C:23]=4[N:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:35])([F:34])[F:36]
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccnc2[nH]ncc12)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(C(=O)c2ccnc3[nH]ncc23)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A mixture of 4-chloro-N-methoxymethyl-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (50 mg, 0.092 mmol) in 4M HCl in dioxane (4 mL) and water (1 mL) was stirred at 70° C. for overnight. Reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by flash chromatography (SiO2, 70% EtOAc-hexanes) to afford 4-chloro-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yi]-3-trifluoromethyl-benzenesulfonamide (28.9 mg) as yellow solid (after lyophilization) in 63% yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[CH3:48][C:49]1[S:50][C:51]([CH:60]([NH2:68])[CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:53]=1>CN(C=O)C>[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([NH:68][CH:60]([C:51]1[S:50][C:49]([CH3:48])=[N:53][C:52]=1[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:38]
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: Cc1nc(-c2ccccc2)c(C(N)Cc2ccccc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(C(Cc2ccccc2)NC(=O)Cc2c[nH]c3ccc(O)cc23)s1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 15B (29.4 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 8.59 (d, J=7.6 Hz, 1H), 7.44-7.22 (m, 5H), 7.07 (dd, J=5.5, 3.2 Hz, 4H), 6.92 (dd, J=6.5, 2.9 Hz, 3H), 6.80 (d, J=2.2 Hz, 1H), 6.55 (dd, J=8.6, 2.3 Hz, 1H), 5.34 (dd, J=15.0, 7.5 Hz, 1H), 3.36 (s, 2H), 3.07 (dd, J=13.8, 7.9 Hz, 1H), 2.84 (dd, J=13.5, 7.0 Hz, 1H), 2.60 (s, 3H); MS (m/z) 468 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([C:18]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][C:25]3[NH:24][N:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.O.[OH-].[Na+]>[C:30]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:26][C:25]3[N:24]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[N:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[CH:20]=[CH:19]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)O)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Temperature: 20 °C
Yield: 63.2 %

Procedure:
A solution of 1 g of p-toluenesulphonyl chloride in 10 cm3 of diethyl ether is added, at a temperature in the region of 20° C., to a solution of 1 g of 6,6-diphenyl-6,7-dihydro-1H-indazol-3-carboxylic acid in 10 cm3 of water and 10 cm3 of a normal aqueous sodium hydroxide solution. The reaction mixture, which sets to a solid after about ten minutes of vigorous stirring, is diluted with 10 cm3 of water. After stirring for about eighteen hours at a temperature in the region of 20° C., the reaction mixture is filtered. The solid is washed with three times 20 cm3 of water and then suspended in 20 cm3 of water. 10 cm3 of a normal aqueous hydrochloric acid solution are added. The mixture is extracted with three times 50 cm3 of ethyl acetate. The combined organic phases are successively washed with three times 70 cm3 of water and once 70 cm3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)]. 0.94 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazol-3-carboxylic acid is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[C@@H:12]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23])[CH2:13][N+:14]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O1CCCC1.O>O1CCCC1>[NH2:14][CH2:13][C@H:12]([C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[OH:23])[C:11]1[CH:24]=[CH:25][CH:26]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H](c1cccc(OCc2ccccc2)c1)[C@H]1CCCC[C@H]1O
Reaction time: 8 h

Procedure:
A solution of 106.6 g (0.3 mol) of rac-(2S*)-2-[(R*)-3-(benzyloxy)-α-(nitromethyl)benzyl]cyclohexanone in 500 ml of dry tetrahydrofuran is added drowpise while stirring within about 3 hours to a suspension of 28.6 g (0.75 mol) of lithium aluminium hydride in 500 ml of dry tetrahydrofuran under argon so that the temperature does not exceed 55°. The reaction mixture is stirred at 50° overnight, treated, after cooling, with 40 ml of ethanol and subsequently with 200 ml of tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The residue is crystallized from methylene chloride/isopropyl ether, there being obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-3-(benzyloxy)benzyl]cyclohexanol in the form of colourless crystals of m.p. 139°-141°.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.BrC1C=COC=1.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>CCCCCC>[O:6]1[CH:10]=[CH:9][C:8]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:7]1
Reactant: C1CCOC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Brc1ccoc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccoc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
69.5 ml of a 1.6 molar solution of n-butyllithium in hexane are mixed with 60 ml of absolute tetrahydrofuran. The mixture is cooled to -60° C. and 10 ml of 3-bromofuran are added dropwise at such a rate that the internal temperature does not exceed -50° C.. When the addition is complete, the whole is stirred for 15 minutes at -60° C. and then 33.2 ml of tributyltin chloride are added dropwise, during the course of which the internal temperature is not allowed to exceed -50° C.. When the addition is complete, the reaction solution is allowed to come to -10° C. and is then stirred for one hour at that temperature. The solution is then carefully quenched with water. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulphate. It is filtered off and the solvent is removed in vacuo. The crude product obtained is purified by distillation in a high vacuum. 30.14 g of (3-furanyl)tributylstannane are obtained in the form of a light-yellow oil (boiling point=100°-104° C. at 0.09 torr).
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]=[C:16]=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N:18]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.C1(C)C=CC=CC=1.C(N(CC)CC)C>O>[F:1][C:2]1[C:14]([NH:15][C:16]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][N:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: C=CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Reactant: CCOC(=O)N1CCCCN1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCn1c(=O)sc2cc(F)c(NC(=O)N3CCCCN3C(=O)OCC)cc21
Yield: 69.6 %

Procedure:
6-Fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-yl isocyanate (1.99 g) and ethyl hexahydropyridazine-1-carboxylate (1.26 g) were added to toluene (8 ml). A catalytic amount of triethylamine was added thereto, and the resultant mixture was stirred at 25° C. for 12 hours. Water was added thereto, and the resultant mixture was extracted with toluene. The extract was washed with water, dried and concentrated to give ethyl 2-[6-fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-ylaminocarbonyl]-hexahydropyridazine-1-carboxylate (2.26 g). m.p., 161.2° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:3].[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:23][C:24]1[N:25]=[CH:26][N:27]=[C:28]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]3[C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:3])[C:29]=1[C:30]#[N:31]
Reactant: COC(=O)c1cccc2nc([C@H](C)N)c(-c3ccccc3)n12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)c(-c3ccccc3)n12
Temperature: 110 °C
Reaction time: 5.5 h

Procedure:
To the crude (S)-methyl 2-(1-aminoethyl)-3-phenylimidazo[1,2-a]pyridine-5-carboxylate (500 mg, 1.69 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (268 mg, 1.69 mmol) in n-butanol (5 mL) was added DIEA (0.5 mL, 2.54 mmol) at 25° C. The reaction mixture was stirred at 110° C. for 5-6 h. The mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-40% acetone in hexane to provide (S)-methyl 2-[1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl]-3-phenylimidazo-[1,2-a]pyridine-5-carboxylate: 1H NMR (400 MHz, DMSO-d6) δ 1.471 (d, J=6.8 Hz, 3H), 3.111 (s, 3H), 5.352-5.420 (m, 1H), 6.935-6.954 (m, 1H), 7.259-7.518 (m, 9H), 7.882-7.941 (m, 2H); LC-MS (ESI) m/z 414.1 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]2([S@:17]([CH3:20])(=[NH:19])=[O:18])[CH2:16][CH2:15]2)[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][CH:28]=[CH:29][C:22]=23)[N:9]=1>CC(OC)(C)C>[CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]2([S@@:17]([CH3:20])(=[NH:19])=[O:18])[CH2:16][CH2:15]2)[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][CH:28]=[CH:29][C:22]=23)[N:9]=1
Reactant: C[C@@H]1COCCN1c1cc(C2([S@](C)(=N)=O)CC2)nc(-c2ccnc3[nH]ccc23)n1
Solvent: COC(C)(C)C
Product: C[C@@H]1COCCN1c1cc(C2([S@@](C)(=N)=O)CC2)nc(-c2ccnc3[nH]ccc23)n1
Yield: 69 %

Procedure:
4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (approximately 10 g, 25 mmol) was suspended in MTBE (500 ml) and stirred at reflux for 2 hours. The suspension was allowed to cool slowly and stirred at RT overnight. The solid was collected by filtration and dried under vacuum to afford the title compound (7.12 g) as a white crystalline solid; 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.44 (1H, dd), 1.47-1.58 (2H, m), 1.76 (1H, dt), 3.11 (3H, s), 3.26 (1H, dd), 3.52 (1H, td), 3.67 (1H, dd), 3.81 (1H, d), 3.85 (1H, d), 4.02 (1H, dd), 4.20 (1H, d), 4.59 (1H, s), 7.00 (1H, s), 7.23 (1H, dd), 7.57-7.62 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.81 (1H, s); m/z: (ES+) MH+, 413.12. Mpt. (Buchi Melting Point B-545) 222° C. Chiral HPLC: (HP1100 System 7, 5 μm Chiralcel OJ (250 mm×4.6 mm) column eluting with Heptane/(EtOH/MeOH 50/50)/TEA 50/50/0.1) Rf, 9.836 99.8%.
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1>CCOC(C)=O.[Cu]I.CS(C)=O>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=2)[N:3]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: Brc1nc[nH]n1
Agent: [Cu]I
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Temperature: 100 °C

Procedure:
To a 250 mL reaction flask was added 3-bromo-1H-1,2,4-triazole (5 g, 33.8 mmol), copper(I) iodide (0.644 g, 3.38 mmol) and cesium carbonate (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with N2, then DMSO (33.8 ml) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 20 h. The reaction was cooled to room temperature, diluted with EtOAc and filtered through a plug of Celite. The Celite was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash chromatography (silica/EtOAc/Hex) yielded 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole as an off white solid (3.78 g, 12.27 mmol, 72.6%): mp 69-70° C.; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −58.04; EIMS m/z 307.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:10]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:17])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCN1
Yield: 90.3 %

Procedure:
Sulfonylation of piperazine-2-one (326.2 mg, 3.3 mmol) with 3,4-dichlorobenzene-sulfonyl chloride (800 mg, 3.3 mmol) was carried out according to a similar procedure described for example 15A using anhydrous dichloromethane (8 mL) as solvent and diisopropylethylamine (1.42 mL, 8.2 mmol) as base. 4-(3,4-dichloro-benzenesulfonyl)-piperazin-2-one was obtained in 90.3% yield (912 mg) as white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.17-3.24 (m, 2H) 3.25-3.30 (m, 2H) 3.59 (s, 2H) 7.79 (dd, J=8.46, 2.15 Hz, 1H) 7.94 (d, J=8.34 Hz, 1H) 8.06 (d, J=2.02 Hz, 1H) 8.08 (s, 1H).