Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH2:21].CO.C(OCC)(=O)C>C1COCC1>[NH2:21][C:15]1[CH:16]=[CH:17][C:18]([I:20])=[CH:19][C:14]=1[CH2:13][OH:12]
Reactant: COC(=O)c1cc(I)ccc1N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(I)cc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of diisobutylaluminium hydride (210 cm3 of a 1.5M solution in THF) was added at -30° to a stirred solution of methyl-2-amino-5-iodobenzoate (28.0 g) in THF (100 cm3) under nitrogen. The mixture was warmed to room temperature, stirred for 16 hours and treated with methanol (35 cm3). Ethyl acetate (500 cm3) was added and the mixture filtered to remove inorganic material. The filtrate was concentrated in vacuo to afford a solid which was chromatographed on silica (Merck "MK 60.9385") eluting wiht chloroform:methanol, 49:1 (by volume), and the requisite fractions were combined and evaporated in vacuo to give 2-amino-5-iodobenzyl alcohol, m.p. 125°, (19.0 g).
Reaction SMILES: C(OC([N:8]([CH:38]([CH3:40])[CH3:39])[C@H:9]1[CH2:14][C@@H:13]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C@@H:12]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C@@H:12]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:11][CH2:10]1)([CH3:39])[CH3:40]
Reactant: CC(C)OC(=O)[C@@H]1C[C@H](N(C(=O)OC(C)(C)C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](C(=O)OC(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Step 1 product (120 mg) in CH2Cl2 is treated with CF3COOH (7 ml) and stirred at room temperature for 2 hours. The solution was evaporated and the residue neutralized with 1 N NaOH and extracted into CH2Cl2. The extract was washed with water, brine, dried over Na2SO4, filtered and the solvent evaporated to give 90 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ(TMS): 8.12 (s, 1 H), 8.02 (d, J=7.8 Hz, 1 H), 7.76 (d, J=7.8 Hz, 1 H), 7.57 (t, J=7.8 Hz, 1 H), 7.35 (bt, 1 H), 6.96 (bd, 1 H), 4.93 (m, 1 H), 4.51 (m, 1 H), 4.12 (d, J=4.8 Hz, 2 H), 3.03 (m, 1 H), 2.77 (m, 1 H), 2.61 (m, 1 H), 2.31 (bs, 1 H), 2.04 (m, 2 H), 1.80-1.30 (m, 4 H), 1.17 (m, 6 H), 1.08 (d, J=6.2 Hz, 6 H). MS found: (M+H)+=472.36.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH2:15]([O:17][C:18]([C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=O)=[O:19])[CH3:16].C(N(CC)CC)C>C(O)C>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:19])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)C(=O)c1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21)c1ccc[nH]1
Temperature: 25 °C

Procedure:
Alternatively, a mixture of 5-aminosulfonylindolin-2-one (1.0 g, 4.7 mmol), 2-ethoxycarbonylcarbonylpyrrole (2.5 g, 14.5 mmol) in ethanol (120 mL) was treated with triethylamine (1.0 mL, 7.2 mmol). The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated to approximately 20 mL, treated with additional triethylamine (0.2 mL, 1.44 mmol) and refluxed for 55 hoursr. The reaction was then cooled to ambient temperature and concentrated. Reverse phase HPLC using acetonitrile/water afforded 5-aminosulfonyl-3-[(pyrrol-2-yl)(ethoxycarbonyl)methylene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 1.35 (t, 3H), 4.50 (q, 2H), 6.40 (s, 1H), 6.65 (s, 1H), 7.06 (d, 1H), 7.25(s, 2H), 7.48 (br s, 1H), 7.50 (s, 1H), 7.68 (d, 1H), 11.50 (s, 1H) ppm; (45 mg) and 5-aminosulfonyl-3-[(pyrrol-2-yl)(carboxy)methylene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 6.40 (s, 1H), 6.65 (s, 1H), 7.06 (d, 1H), 7.25 (s, 2H), 7.48 (br s, 1H), 7.68 (d, 1H), 7.85 (s, 1H), 11.50 (s, 1H) ppm; (48 mg).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:42]12([C:48]3[C:49]([O:53][C:54]4[N:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=4)=[CH:50][CH:51]=[CH:52][C:47]=3[O:46][CH2:45]1)[CH2:44][CH2:43]2>>[C:42]12([C:48]3[C:49]([O:53][C:54]4[N:59]=[CH:58][C:57]([NH:60][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:56][CH:55]=4)=[CH:50][CH:51]=[CH:52][C:47]=3[O:46][CH2:45]1)[CH2:44][CH2:43]2
Reactant: Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (94 mg, 0.462 mmol) in dry N,N-Dimethylformamide (2 mL) DIPEA (0.115 mL, 0.661 mmol) and then TBTU (159 mg, 0.496 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature. 6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinamine (Reference Intermediate 216, 84 mg) was added and the reaction mixture was stirred for 6 hours at the same temperature. The reaction was quenched with brine (2 ml), diluted with water (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was washed with ice cold brine (2×5 ml), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound as a colourless oil (130 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([OH:23])[CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: O=C(O)c1cccc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (5)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and 3-hydroxybenzoic acid as brown solid (41%). MS 424 (MH+).
Reaction SMILES: N1C2C(=CC=CC=2S([O:14][C:15]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:26]4[C:31]([CH:32]=3)=[CH:30][C:29]([CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:28][CH:27]=4)=[C:20]3[C:16]=2[CH2:17][NH:18][C:19]3=[O:47])(=O)=O)C=CC=1.Cl.CO>>[OH:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][CH:27]=3)=[C:20]2[C:16]=1[CH2:17][NH:18][C:19]2=[O:47]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc4cccnc34)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 47.9 %

Procedure:
In a similar manner to Step 2 of Example 233, 4-(8-quinolinesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0164 g, 0.0251 mmol) was treated with 10% hydrogen chloride-methanol solution (0.650 mL) to obtain Compound 269 (0.00555 g. yield 40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:55][C:56]1([CH3:78])[CH2:61][CH2:60][CH2:59][N:58]([CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[CH:70][C:69]([CH:72]3[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]3)=[CH:68][CH:67]=2)[CH2:57]1>CN(C=O)C>[CH3:55][C:56]1([CH3:78])[CH2:61][CH2:60][CH2:59][N:58]([CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[CH:68][C:69]([CH:72]3[CH2:73][CH2:74][N:75]([C:16]([C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:19])=[CH:7][CH:8]=4)=[O:18])[CH2:76][CH2:77]3)=[CH:70][CH:71]=2)[CH2:57]1
Reactant: CC1(C)CCCN(CCCOc2ccc(C3CCNCC3)cc2)C1
Reactant: COC(=O)CCc1ccc(C(=O)O)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(C(=O)N2CCC(c3ccc(OCCCN4CCCC(C)(C)C4)cc3)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
A solution of 4-[3-(methyloxy)-3-oxopropyl]-1-naphthalenecarboxylic acid (for example as prepared for Intermediate 6) (0.197 g, 0.76 mmol) in anhydrous DMF (2 ml) was treated with HBTU (0.29 g 0.77 mmol), diisopropylethylamine (0.6 ml, 3.82 mmol), the mixture was stirred at room temperature for 20 minutes, 3,3-dimethyl-1-(3-{[4-(4-piperidinyl)phenyl]oxy}propyl)piperidine dihydrochloride (for example as prepared for Intermediate 4) (250 mg, 0.63 mmol) was added and the mixture stirred at room temperature for 4 h. The mixture was evaporated to dryness and purified on a SCX-2 cartridge (5 g) eluting with MeOH, followed by 2M ammonia solution in methanol to afford the title compound (238 mg). LCMS RT=2.79 min, ES+ve m/z 571.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([NH:25][C:26]4[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.C(OCC)(OCC)O[CH2:36][CH3:37]>CN(C=O)C>[CH3:1][N:2]([CH3:33])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][C:14]([N:25]4[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]=[C:36]4[CH3:37])=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Nc4ccccc4N)nc(N4CCOCC4)c3s2)CC1
Reactant: CCOC(OCC)OCC
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Temperature: 150 °C
Yield: 23.9 %

Procedure:
A mixture of N-[6-(4-dimethylaminopiperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]benzene-1,2-diamine (80 mg, 0.17 mmol) and triethyl orthoformate (1 mL, 6.0 mmol) in DMF (1 mL) was heated at 150° C. for 6 h. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:2 M NH3 in MeOH 100:0 to 98:2 to 95:5) followed by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 117 as a white solid (20 mg, 24%). LCMS (Method F): RT=4.24 min, [M+H]+ 492.3. 1H NMR (CDCl3, 400 MHz): δ 8.09-8.04 (m, 1 H); 7.74-7.68 (m, 1 H); 7.29-7.24 (m, 3 H); 4.08-4.02 (m, 4 H); 3.91-3.86 (m, 4 H); 3.83 (s, 2 H); 3.08-3.00 (m, 2 H); 2.93 (s, 3 H); 2.30 (s, 6 H); 2.21-2.10 (m, 3 H); 1.88-1.79 (m, 2 H); 1.68-1.53 (m, 2 H)
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](N3CC4CN(C(OC(C)(C)C)=O)CC4C3)[N:15]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:14]=2[CH:38]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:40](F)(F)[C:41](O)=O>O>[CH:10]1([C:16]2[N:15]([CH2:33][CH:34]=[C:35]([CH3:36])[CH3:37])[C:14]3[CH:38]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[N:17]=2)[C:38]2=[CH:14][NH:15][CH2:40][CH:41]2[CH2:1][NH:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc(NC(=O)c3ccccc3)cc21
Solvent: O
Product: CC(C)=CCn1c(C2NCC3CNC=C32)nc2ccc(NC(=O)c3ccccc3)cc21
Yield: 95 %

Procedure:
10 mg (0.02 mmol) of tert-butyl 5-[6-benzoylamino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate were dissolved in 200 μl of trifluoroacetic acid and 200 μl of water, and stirred at room temperature for 19 hours. The reaction mixture was diluted with water and freeze-dried. 10 mg (95%) of the desired product were obtained.
Reaction SMILES: [C:1]1([OH:21])[C:2]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[C:22](O)([CH3:25])([CH3:24])[CH3:23].FC(F)(F)S(O)(=O)=O>ClC1C=CC=CC=1Cl.O.CCOCC>[C:22]([C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:1]([OH:21])[C:2]=1[C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: Oc1c(-c2ccc3c(c2)CCCC3)ccc2c1CCCC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1cc2c(c(O)c1-c1ccc3c(c1)CCCC3)CCCC2
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A mixture of 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol (1.0 g, 3.4 mmol), tert-butyl alcohol (1.4 g), trifluoromethanesulfonic acid (0.04 g) was dissolved in 2 ml 1,2-dichlorobenzene. The mixture was heated at 120° C. for 2.5 hours. GC showed 97% conversion to 87% mono-butylated product, and 10% bis-butylated product. The mixture was cooled, and diluted with 10 ml water and 10 ml ether. The layers were separated, and the organic layer was washed with sodium bicarbonate solution, dried, and concentrated. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate/hexanes) to yield 0.7 g of white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:39])(=[N:27][C:28](=[O:38])[NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:26])=[CH:21][CH:20]=1>>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:39])=[O:26])=[O:38])=[CH:35][CH:34]=1
Reactant: COc1ccc(NC(=O)N=S(C)(=O)c2ccc(N)cc2)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: COc1ccc(NC(=O)N=S(C)(=O)c2ccc(Nc3ncc(-c4cccs4)c(N[C@H](C)CO)n3)cc2)cc1
Yield: 30 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (200 mg, 0.74 mmol) with (RS)—S-(4-aminophenyl)-N-(4-methoxy-phenylcarbamoyl)-S-methylsulphoximide (214 mg, 0.67 mmol) according to procedure 5c, the desired product is obtained in 30% yield (110 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:15][CH:16]=2)=[N:7][CH:8]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]#[C:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:30])[F:1])=[CH:8][N:7]=3)=[CH:16][N:15]=2)[CH2:18][CH2:19]1)(=[O:49])=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a stirred solution of tert-butyl 4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazine-1-carboxylate (724 mg, 1.67 mmol) in CH2Cl2 (8 mL) at 0° C. was added trifluoroacetic acid (4 mL). The reaction was brought to room temperature and stirred for 30 minutes. Volatiles were removed in vacuo. The residue was then dissolved in CH2Cl2 (20 mL) and washed with aqueous sodium hydroxide solution (2M, 2×20 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (3×10 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), and cooled to 0° C. and treated sequentially with triethylamine (0.25 mL, 1.75 mmol) and methanesulfonyl chloride (0.14 mL, 13.5 mmol). The reaction was brought to RT and stirred for 1 hour. The reaction was then quenched with water (50 mL). The layers were separated and the aqueous phase extracted with CH2Cl2 (3×20 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo to give 1-(methylsulfonyl)-4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazine as an orange solid (445 mg, 1.08 mmol, 65%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH:9][CH3:10])=[O:8])[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31](=O)[CH2:32][C:33](OCC)=[O:34])=[CH:30][C:25]=2[N:24]=[N:23]1>CCCCO>[NH:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[NH:1][C:2]4[N:6]([N:5]=[C:4]([C:7]([NH:9][CH3:10])=[O:8])[N:3]=4)[C:33](=[O:34])[CH:32]=3)=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: CNC(=O)c1n[nH]c(N)n1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CNC(=O)c1nc2[nH]c(-c3ccc4[nH]nnc4c3)cc(=O)n2n1
Reaction time: 12 h
Yield: 18.1 %

Procedure:
To a solution of 5-amino-N-methyl-1H-1,2,4-triazole-3-carboxamide (100 mg, 0.71 mmol) in n-BuOH (3 ml) was added TsOH (4.8 mg, 0.03 mmol), ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (230 mg, 0.88 mmol). The resulting solution was stirred for 12 h at reflux. The solids were collected by filtration to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-N-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-α]pyrimidine-2-carboxamide as a white solid (39.8 mg, 18%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[CH3:14][S:15](Cl)(=[O:17])=[O:16].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:11]([NH:12][S:15]([CH3:14])(=[O:17])=[O:16])=[C:2]([CH3:1])[C:3]([O:4][CH2:5][C:6]#[N:7])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(OCC#N)ccc(Cl)c1N
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
To a solution of crude (2-methyl-3-amino-4-chlorophenoxy)acetonitrile (11.53 g) in toluene (PhMe) (60 mL) was added methanesulfonyl chloride (MsCl) (4.5 mL, 6.7 g) and the resultant solution was warmed to 35-40° C. Pyridine (py) (4.7 mL, 4.6 g) was then added slowly over 2 h. The resultant mixture was permitted to cool to ambient temperature and stirred for 24 h. The crude product mixture was then partitioned between 1N hydrochloric acid (100 mL), and a mixture of ethyl acetate (300 mL) and tetrahydrofuran (100 mL). The organic phase was washed with water, then concentrated to ca. 200 mL, leading to crystallization of the desired product. The white crystalline product was collected, rinsed with toluene, and dried to afford 10.40 g (65.1% field) of N-(6-chloro-3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (>97% pure by HPLC). This material could optionally be recrystallized from isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH2:20])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C=O.[OH-].[Na+].[C:35](=O)([O-])[O-:36].[Na+].[Na+]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH:20][CH2:35][OH:36])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)sulfonyl](2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (150 mg, 0.34 mmol) obtained in Example 39 in ethylene glycol dimethyl ether (3 ml), an aqueous solution of formaldehyde (37%, 0.1 ml) and 5% aqueous sodium hydroxide (0.4 ml) were added at 0° C., and the mixture was stirred overnight at room temperature. Sodium carbonate (20 mg) was added to the reaction mixture, and the mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure, and then the residue was dissolved in chloroform, dried over magnesium sulfate, and filtered. Subsequently, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, and then was collected by filtration, to obtain the title compound (93 mg, 0.20 mmol, 58%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[F:22][C:23]([F:34])([F:33])[S:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.[H-].[Na+]>>[F:21][C:2]([F:20])([F:1])[S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([S:24][C:23]([F:34])([F:22])[F:33])=[CH:26][CH:27]=2)[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Reactant: O=C(NCc1ccc(SC(F)(F)F)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(c1ccccc1)N(Cc1ccc(SC(F)(F)F)cc1)Cc1ccc(SC(F)(F)F)cc1
Yield: 81 %

Procedure:
N-(4-trifluoromethylthiobenzyl)benzamide (100 mg, 0.32 mmol) was coupled with 4-(trifluoromethylthio) benzyl bromide (91 mg, 0.34 mmol) using sodium hydride (9.2 mg, 0.38 mmol) to give 130 mg (80%) of N,N-bis(4-trifluoromethylthiobenzyl)benzamide as a yellow oil. 1HNMR (360 MHz, DMSO-d6) δ 7.65 (m, 4H), 7.31-7.47 (m, 9H), 4.57-4.66 (m, 4H). MS-EI m/z 501 [M+].
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:13]=[C:12]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=2)[C:9]=1[C:10]#[N:11].C1COCC1.[O:42]=[C:43]1[O:47][CH:46]([C:48](Cl)=[O:49])[CH2:45][CH2:44]1>C(#N)C>[NH2:7][C:8]1[C:9]([C:10]#[N:11])=[C:12]([C:30]2[CH:31]=[C:32]([NH:36][C:48]([CH:46]3[CH2:45][CH2:44][C:43](=[O:42])[O:47]3)=[O:49])[CH:33]=[CH:34][CH:35]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[N:15]=1
Reactant: O=C1CCC(C(=O)Cl)O1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(N)c2)c(C#N)c(N)n1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(NC(=O)C3CCC(=O)O3)c2)c(C#N)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a cold (0° C.) mixture of pyridine (0.20 mL, 2.424 mmol), 2-amino-4-(3-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)nicotinonitrile (starting compound 2, 1.010 g, 2.424 mmol), acetonitrile (10 mL) and THF (2 mL) was added dropwise a solution of 5-oxotetrahydro-2-furancarbonyl chloride (0.360 g, 2.424 mmol) in acetonitrile (4 mL). The mixture was stirred for 2 hrs., allowed to warm to room temperature, stirred for 1 hr., and extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (hexane:Ethyl acetate, 7:3-5:5) to give N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-5-oxotetrahydro-2-furancarboxamide as a white solid (0.982 g, yield 77%).