Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[Cl:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([NH2:26])[CH:20]=[CH:21][CH:22]=2)[N:17]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:26][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[C:16]([Cl:15])[CH:25]=[CH:24]3)(=[O:10])=[O:9])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Nc1cccc2ccc(Cl)nc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Yield: 22.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-chloro-2-nitrobenzene-1-sulfonyl chloride (Intermediate 454) (0.86 g, 3.37 mmol), 2-chloro-quinolin-8-ylamine (Intermediate 26) (0.5 g, 2.80 mmol), DMAP (cat), pyridine (0.68 ml, 8.42 mmol) and DCM (10 ml) gave the title compound (0.25 g, 23%) after purification by column chromatography DCM/MeOH (99:1) as the eluent.
Reaction SMILES: C(=O)(O)[O-].[Na+].[N:6]1[CH:11]=[CH:10][C:9]([SH:12])=[N:8][C:7]=1[SH:13].Cl.[CH2:15]([S:23]SC(=N)N)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O.CO>[CH2:15]([S:23][S:13][C:7]1[N:8]=[C:9]([S:12][S:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:10]=[CH:11][N:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCSSC(=N)N
Reactant: Sc1ccnc(S)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCSSc1ccnc(SSCCCCCCCC)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of sodium bicarbonate (4.30 g; 0.05 mole) in water (60 ml) was added dropwise to a stirred suspension of pyrimidine-2,4-dithiol prepared as above (2.16 g, 0.015 mole) and S-n-octylthioisothiourea hydrochloride obtained in step (A) (7.695 g, 0.03 mole) in methanol (70 ml) at 60°-65° C. over 30 minutes. The mixture was stirred at room temperature for a further hour and then extracted into naphtha (3×50 ml). The organic extracts were washed with water, dried using anhydrous MgSO4 and evaporated yielding the product as an orange oil (5.54 g; 85%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C(C=P(CCCC)(CCCC)CCCC)#N.[C:47]1([SH:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Reactant: Sc1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSc2ccccc2)C1=O
Temperature: 110 °C

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (180 mg, 0.403 mmol; Example 91, Step B) in 2 mL of toluene was added cyanomethylenetributylphosphorane (324 uL, 1.21 mmol) and benzenethiol (121 μL 1.21 mmol) at RT. The mixture was heated to 110° C. for 2 h. The reaction was cooled down, quenched (sat. aq. NH4Cl solution), extracted (2×EtOAc), and washed with brine. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10, 20, 40% EtOAc/hexane) provided the title compound.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][C:37]([Si:40]([CH3:54])([CH3:53])[O:41][CH2:42][C@@H:43]1[CH2:52][N:51]2[C@H:46]([CH2:47][O:48][CH2:49][CH2:50]2)[CH2:45][NH:44]1)([CH3:39])[CH3:38].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[C@H:43]([CH2:42][O:41][Si:40]([C:37]([CH3:39])([CH3:38])[CH3:36])([CH3:53])[CH3:54])[CH2:52][N:51]4[C@H:46]([CH2:47][O:48][CH2:49][CH2:50]4)[CH2:45]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Reactant: Cc1ccncc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccncc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 74.9 %

Procedure:
The 2-[3,5-bis(trifluoromethyl)phenyl]-N-(6′-chloro-4-methyl-3,4′-bipyridin-3′-yl)-N,2-dimethylpropanamide (D52, 77 mg, 0.15 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 51.5 mg, 0.18 mmol), sodium t-Butoxide (18 mg, 0.19 mmol) were degassed together in dry toluene (1.5 mL) for 5 mins before adding Bis(dibenzyleneacetone) Palladium (9 mg, 0.015 mmol) and 2-Dicyclohexylphosphino-2′-(N′N′-dimethylamino)biphenyl (15 mg, 0.038 mmol) and heating under microwave conditions at 130° C. for 30 mins. Diluted with EtOAC, washed with sat. NaHCO3×1, brine ×1, dried (MgSO4). Filtered. Solvent evaporated. Residue purified eluting with Pent to EtOAc. No Fractions isolated clean. Mixed fractions combined, solvent evaporated and residue re-purified on a 2 g SCX column, washing with MeOH (2×10 mL) before eluting the compound off with NH3 in MeOH (3×10 mL). Solvent evaporated under reduced pressure to afford a gummy solid (86 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:14][O:15][C:16](=[O:41])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:25](=[O:34])[C:26]#[C:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:18]=1>>[CH3:14][O:15][C:16](=[O:41])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)/[C:26](=[C:27](/[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)\[C:2]3[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=3)/[C:25]2=[O:34])[CH:18]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: COc1cc(I)cc(OC)c1OC
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cc(OC)c(OC)c(OC)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 5-Iodo-1,2,3-trimethoxy-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.76 (s, 6H), 3.91 (s, 3H), 3.94 (s, 3H), 4.96 (s, 2H), 6.55 (s, 2H), 6.61-6.71 (m, 4H), 7.06 (t, 1H), 7.38-7.40 (m, 5H), 7.53 (d, 1H), 7.91 (d, 1H), 8.02 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].C(OCC)(=O)C>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[F:2])[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: O=c1[nH]cc(-c2ccncc2F)c(=O)[nH]1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccncc2F)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
5-(3-Fluoro-pyridin-4-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep 67, 243 mg, 1.1 mmol) was dissolved in DMF (2 ml). K2CO3 (153 mg, 1.1 mmol) was added and the mixture was stirred at room temperature for 1 hour. 3-Bromo-1,1dimethoxy-propane (225 mg, 1.11 mmol) was then added and after stirring the reaction at room temperature for 48 hours, the reaction was left at 4° C. for 17 days. Ethyl acetate was then added and the mixture washed with water and brine. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography with DCM-MeOH—NH4OH 98-2-0.2 to afford 75 mg of the title compound (22% yield).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[CH3:39][CH:40]([O:42][CH2:43][CH2:44][NH2:45])[CH3:41].NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:45][CH2:44][CH2:43][O:42][CH:40]([CH3:41])[CH3:39])=[O:34])[C:15]1=[O:38]
Reactant: CC(C)OCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.143 g, 0.28 mmol) in EtOH (3 mL) under nitrogen was treated with 2-[(1-methylethyl)oxy]ethanamine (0.102 mL, 0.83 mmol) for 50 min. (130° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (35 mL), and treated with hydrazine (0.174 mL, 5.55 mmol) for 4 h@50° C. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (150 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 3:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.2 Hz, 6 H), 2.8 (bs, 2 H), 3.3 (s, 2 H), 3.5 (m, 4 H), 3.6 (m, 1 H), 4.2 (s, 2 H), 7.1 (t, J=9.3 Hz, 2 H), 7.4 (dd, J=8.5, 5.4 Hz, 2 H), 8.1 (s, 1 H), 8.5 (s, 1 H), 10.4 (s, 1 H); ES+ MS: 443 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.[NH2:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][S:18]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(c1ccccn1)c1ccccn1
Solvent: CCO
Product: O=C(O)C1CSC(c2ccccn2)(c2ccccn2)N1
Yield: 11 %

Procedure:
A mixture of 3.68 g of di-2-pyridyl ketone, 2.42 g of L-cysteine, 25 ml of ethanol was refluxed for 3.5 hours. After allowing the mixture to cool, the insoluble matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed in sequence with ethyl acetate and ether to give 0.63 g of 2,2-di(2-pyridyl)-thiazolidine-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:21][CH2:20][CH2:19][C:18]#[C:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][S:10][C:11]=3[CH:16]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: Clc1ccc(-c2nsc3cc(C#CCCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 18, Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Azetidine were converted to yield 6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-chloro-phenyl)-benzo[d]isothiazole, MS: 367 (MH+).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]([CH3:19])[NH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:2]1([NH:8][C:9]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:19])[NH:11][N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1c(NC2CCCCC2)n[nH]c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCO
Product: Cc1[nH]nc(NC2CCCCC2)c1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 2 g (0.007 mole) of 3-cyclohexylamino-5-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester hydrochloride [1:1] in 30 mL of ethanol was treated with 5 mL of 50% sodium hydroxide solution, 20 mg of tetrabutylammonium bromide and stirred rapidly while heating at reflux. After 20 hr the reaction mixture was diluted with ice water, extracted with 6×100 mL of isopropyl ether, the pH adjusted to 7 with concentrated sulfuric acid and to pH 5.5 with 10 g of sodium dihydrogen phosphate. The fine precipitate was collected by filtration to give 0.6 g of beige power, mp 162°-163° C. (degasses).
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)C.[CH3:10][C:11]([CH3:28])([O:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=CC=C[CH:20]=1)=[O:15])[CH3:12].N[C@H](C(OC)=O)CC(C)C.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:10][C:11]([CH3:28])([O:13][C:14]([NH:16][C@H:17]([C:25]([O:27][CH3:1])=[O:26])[CH2:18][CH:19]([CH3:24])[CH3:20])=[O:15])[CH3:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COC(=O)[C@@H](N)CC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of diisopropylethylamine (8.7 ml., 50 mmole) in tetrahydrofuran (50 ml.) is added dropwise to a mixture of N-[(1,1-dimethylethoxy) carbonyl]-L-phenylalanine (13.265 g., 50 mmole), L-leucine, methyl ester (9.085 g., 50 mmole) and 1-hydroxybenzotriazole hydrate (7.65 g., 50 mmole) in tetrahydrofuran (100 ml.) at 0°. This is followed by the addition of dicylcohexylcarbodiimide (10.315 g., 50 mmole). The reaction is stirred at 0°for 2 hours and left stirring overnight at room temperature. The nexy day, the precipitated dicyclohexyl urea is filtered off, the solvents are stirred down and the residue is diluted with ethyl acetate (200 ml.). The organic solution is washed sequentially with saturated aqueous sodium bicarbonate solution (2×100 ml.) and saturated aqueous sodium chloride (2×100 ml.), dried over sodium sulfate, filtered, and concentrated to give crude product. Crystallization from ethyl ether gives 7.05 g. of pure product. Concentration of the mother liquor solutions gives 4.57 g. of crystalline product. An additional 1.35 g. of product is obtained by chromatographic purification of the crude product obtained from the left-over mother liquors (40 g. silica gel, eluting with 4:1 hexane:ethyl acetate). Thus, a total of 12.96 g. of N-[N-[(1,1 -dimethylethoxy)carbonyl]-L-leucine, methyl ester is obtained;
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[Cl:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.[NH2:47][C:48]([CH3:68])([CH3:67])[C:49]([N:51]1[CH2:56][CH2:55][N:54](C(OCC2C=CC=CC=2)=O)[CH2:53][CH2:52]1)=[O:50].C(N1CCNCC1)C1C=CC=CC=1>>[Cl:43][C:32]1[CH:33]=[C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49]([N:51]2[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]2)=[O:50])([CH3:68])[CH3:67])[CH:35]=[CH:36][C:31]=1[CH2:30][C:29]1[C:25]([O:24][C@@H:6]2[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]2[OH:4])=[N:26][NH:27][C:28]=1[CH:44]([CH3:46])[CH3:45]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: c1ccc(CN2CCNCC2)cc1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)cc1Cl

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-chlorophenyl}methyl)-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzylpiperazine, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][N:34]([CH3:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.C(O)(=O)/C=C\C(O)=O>N1C=CC=CC=1.CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:40])[C:38]4[CH:37]=[CH:36][C:35]([N:34]([CH3:33])[CH3:44])=[CH:43][CH:42]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(N(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.15 mmol) in pyridine (5 ml) was added 4-(dimethylamino)benzoylchloride (420 mg, 2.28 mol) dropwise. The solution was stirred overnight, the solvent evaporated and the residue partitioned between dichloromethane and 2N NaOH solution. The aqueous layer was extracted with dichloromethane (×3). The organics were dried, filtered and evaporated to leave a solid which was triturated with EtOAc/Et2O (1:4) to leave a solid which was dissolved in EtOAc and treated with maleic acid (3 eqs.) to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide (320 mg, 30%). 1H NMR (d6-DMSO)): δH 9.05 (1H, s), 8.25 (1H, s), 8.18 (1H, d, J=8 Hz), 7.84 (2H, d, J=9.2 Hz), 7.29 (1H, s), 7.25 (1H, d, J=8 Hz), 6.78 (2H, d, J=8.8 Hz), 6.17 (6H, s), 4.71 (1H, m), 3.95 (3H, s), 3.01 (6H, s), 2.83-3.18 (9H, m), 2.68 (3H, s), 2.08 (6H, m), 1.56 (2H, m). HPLC (5.23 mins, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:10]=1)=O)C.[NH3:20]>CO>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH:10]=[C:6]([C:4]([NH2:20])=[O:3])[N:7]=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2cccc(F)c2F)cn1
Reactant: N
Solvent: CO
Product: NC(=O)c1cn(Cc2cccc(F)c2F)cn1

Procedure:
5.34 g of 1-(2,3-difluorobenzyl)-imidazole-4-carboxylic acid ethyl ester are dissolved in 80 ml of methanol and transferred to an autoclave. 20.0 g of ammonia are introduced under pressure and the whole is heated at 100° for 19 hours. When the excess ammonia has been blown off, the resulting product is filtered off and recrystallised from ethanol. 1-(2,3-difluorobenzyl)-imidazole-4-carboxamide having a melting point of 221°-222° is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: C[C@H]1CCCN1
Product: C[C@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B53 was prepared following the general procedure reported for B10 using A1 and (S)-2-methylpyrrolidine; yield: 195.5 mg (56%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.17 and 1.24 (2 d, J=6.3 Hz, 3H), 1.60-1.70 (m, 1H), 1.82-2.08 (m, 3H), 3.38-3.64 (m, 2H), 4.12-4.29 (m, 1H), 4.18 (s, 2H), 6.82 (2 s, 2H), 6.94-7.00 (m, 1H), 7.25 (t, J=7.9 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.83-7.90 (m, 1H), 8.18 (s, 1H), 9.58 (s, 1H). MS (ES) C15H20N6O2S requires: 348. found: 349 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([S:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.C(Cl)(Cl)[Cl:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:18][CH2:6][CH2:5][CH:4]1[CH2:3][N:2]([CH3:1])[C:14](=[O:16])[C:13]2[CH:12]=[CH:11][CH:10]=[N:9][C:8]=2[S:7]1
Reactant: CN1CCC(Sc2ncccc2C(=O)O)C1
Reactant: ClC(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CN1CC(CCCl)Sc2ncccc2C1=O

Procedure:
A mixture of 80.75 g (0.34 mole) of 2-[(1-methyl-3-pyrrolidinyl)thio]-3-pyridinecarboxylic acid, 500 ml of chloroform, 200 g of carbon tetrachloride and 178 g (0.68 mole) of triphenylphosphine was stirred at reflux for 2.5 hr. The resulting solution was extracted with one 500 ml and three 125 ml portions of 1N hydrochloric acid. The acid extracts were combined and extracted with isopropyl ether. The aqueous layer was basified with sodium hydroxide and extracted three times with chloroform. The combined chloroform extract was dried over sodium sulfate and concentrated. A portion of the residue was chromatographed on the high pressure liquid chromatograph using a silica column and ethyl acetate. The compound obtained was crystallized from isopropyl ether-isopropyl alcohol, m.p. 97°-100° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][NH:4][CH2:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7].[C:15]([O:19][C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)[CH3:25])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][NH:4][CH2:3][CH:2]([CH3:14])[CH3:1])[CH2:28][CH2:27]1)[CH3:25])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)CNC[C@H](N)c1ccccc1
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Product: CC(C)CNC[C@H](NC1CCN(C(C)CCNC(=O)OC(C)(C)C)CC1)c1ccccc1
Yield: 58.2 %

Procedure:
Using general procedure A, (R) —N2-(2-methylpropyl)-1-phenyl-ethane-1,2-diamine (350 mg, 1.82 mmol) and [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (493 mg, 1.83 mmol) afforded {3-[4-((R)-2-(2-methylpropyl)amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (473 mg, 58%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C1C2C(COC([N:56]=[C:57]=[S:58])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH2:2]([O:9][C:10]([C@H:12]1[CH2:17][N:16]([C:57](=[S:58])[NH2:56])[CH2:15][CH2:14][N:13]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: NC(=S)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of the compound (2.58 g) obtained in Step 3 in chloroform (26 ml) was added, with stirring at room temperature, triethylamine (896 μl), and 9-fluorenylmethoxycarbonyl isothiocyanate (1.66 g) was added. After stirring overnight at room temperature, piperidine (1.11 ml) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography (5% methanol/chloroform) to give the title compound (2.12 g).