Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[N:8]2[CH2:18][C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: COC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Cl)cc2n1CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a stirred solution of methyl 6-chloroindole-2-carboxylate (9.8 g, 46.7 mmol) (D. Knittel, Synthesis, 1985, 2, 186–188) in DMF (80 mL) under Ar at ambient temperature was added sodium hydride (60%; 2.80 g, 70 mmol) portionwise over 10 min. After 30 min, chloroacetonitrile (5.9 mL, 93.2 mmol) was added dropwise and the resultant mixture was heated at 75° C. (bath temp.) for 45 min; then allowed to cool. The reaction mixture was poured onto ice (500 mL) and the solid product was filtered, washed with ice-cold water (100 mL), and triturated with refluxing ethanol (150 mL). After allowing to cool to ambient temperature, then cooling in ice, the solid product was filtered-off and washed with ice-cold ethanol (50 mL) to afford the title compound (9.49 g, 82%) as a light grey solid: mp 177–8° C.; IR νmax (Nujol)/cm−1; 3094, 2955, 2925, 2854, 1713, 1613, 1568, 1527, 1519, 1448, 1421, 1398, 1378, 1336, 1306, 1260, 1150, 1108, 1060, 943, 908, 834, 802, 761, 737, 682, 618, 597, 518 and 478; NMR δH (400 MHz, DMSO-d6) 3.95 (3H, s), 5.56 (2H, s), 7.22 (1H, dd, J 8.5, 2 Hz), 7.34 (1H, d, J 1 Hz), 7.43 (1H, br s) and 7.62 (1H, d, J 8.5 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:25](O)=[O:26])[CH2:9]2)=[O:7])[CH2:3]1.O[N:29]=[C:30]([NH2:35])[CH2:31][CH2:32][O:33][CH3:34]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:25]3[O:26][N:35]=[C:30]([CH2:31][CH2:32][O:33][CH3:34])[N:29]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
150 mg (0.324 mmol) of the compound from Example 110A and 77 mg (0.649 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 23 mg (15% of theory).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([OH:22])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24]/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([O:22][CH2:24]/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/CBr
Reactant: OC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COC(=O)/C=C/COC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
A mixture of 96C [1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-ol] (63 mg, 0.213 mmol), methyl 4-bromocrotonate (0.075 mL, 0.64 mmol), 2,6-di-tert-butylpyridine (0.334 mL, 1.49 mmol), and AgOTf (164 mg, 0.64 mmol) in DCM (0.5 mL) was stirred at rt in the dark for 3 days. LC-MS showed the presence of the product, and the reaction was filtered. The filtrate was concentrated in vacuo. The crude product was chromatographed [SiO2; continuous gradient of EtOAc/hexane (0% to 10% over 10 min)] to give the title compound (42 mg, 0.106 mmol, 50% yield) as an oil. 1H NMR (CDCl3) δ: 7.28-7.17 (m, 3H), 7.07-6.98 (m, 3H), 6.94-6.86 (m, 3H), 6.78 (ddd, J=8.1, 2.4, 1.0 Hz, 1H), 6.02 (dt, J=15.6, 2.2 Hz, 1H), 4.07 (dd, J=4.2, 2.1 Hz, 2H), 3.84 (t, J=1.4 Hz, 2H), 3.67 (s, 3H), 2.11-2.03 (m, 4H), 1.97-1.88 (m, 2H), 1.86-1.77 (m, 2H).
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[CH2:36]([C:39]1[S:43][C:42](S(N)(=O)=O)=[CH:41][CH:40]=1)[CH2:37][CH3:38]>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31]([NH:7][C:5]([NH:4][S:1]([C:42]3[S:43][C:39]([CH2:36][CH2:37][CH3:38])=[CH:40][CH:41]=3)(=[O:3])=[O:2])=[O:6])=[CH:30][CH:29]=1)[CH:20]=[CH:19]2
Reactant: CCCc1ccc(S(N)(=O)=O)s1
Reactant: NC(=O)N=S(=O)=O
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Product: CCCc1ccc(S(=O)(=O)NC(=O)Nc2ccc(-n3ccc4cc(N)c(F)cc4c3=O)cc2)s1

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-propylthiophene-2-sulfonic acid amide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-5-propylthiophene-2-sulfonamide. ES-MS (M+H)+=515.1; 1H-NMR (DMSO-d6) δ (ppm): 9.06-9.00 (s, 1H), 7.66-7.62 (d, J=12.4 Hz, 1H), 7.62-7.58 (d, J=3.7 Hz, 1H), 7.48-7.42 (m, 2H), 7.32-7.26 (m, 2H), 7.24-7.20 (d, J=7.3 Hz, 1H), 6.96-6-90 (d, J=3.6 Hz, 1H), 6.74-6.66 (d, J=8.4 Hz, 1H), 6.58-6.48 (bs, 1H), 6.50-6.46 (d, J=7.3 Hz, 1H), 2.84-2.76 (m, 5H), 1.68-1.56 (tq, J=7.3, 7.6 Hz, 2H), 0.94-0.86 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:17]=[C:18]([C@@:22]2([O:29][CH3:30])[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:15][C:16]3[CH:17]=[C:18]([C@@:22]4([O:29][CH3:30])[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]4)[CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: CO[C@]1(c2cccc(O)c2)CCO[C@@H](C)C1
Product: CO[C@]1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCO[C@@H](C)C1
Yield: 69 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (2S,4R)-4-(3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran to give (2S,4R)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-4-methoxy-2-methyltetrahydropyran in 69% yield, m.p. 88°-90° C.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:29][CH3:30])=[C:9]([O:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([N:19]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])[CH3:20])[CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][NH:3]1.S(Cl)([Cl:33])=O>CN(C)C=O>[ClH:33].[Cl:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:29][CH3:30])=[C:9]([O:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([N:19]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])[CH3:20])[CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1O[C@H]1CC[C@@H](N(C)C(=O)N2CCOCC2)CC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1O[C@H]1CC[C@@H](N(C)C(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
800 mg of 3,4-dihydro-4-oxo-6-[cis-4-(N-morpholinocarbonyl-N-methyl-amino)-cyclohexyl-oxy]-7-methoxy-quinazoline, 7 ml of thionyl chloride and 0.1 ml dimethylformamide are refluxed for 3 hours. The volatile components of the reaction mixture are eliminated using the rotary evaporator, the residue is combined with toluene and concentrated again by rotary evaporation.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20]N)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1.[C:31]([BH3-])#[N:32].[Na+].[CH2:35]=O>C(#N)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20][N:32]([CH3:31])[CH3:35])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1
Reactant: NCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Reactant: [BH3-]C#N
Reactant: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)isochroman-1-yl)ethanamine (25 mg, 0.058 mmol) and sodium cyanoborohydride (18.1 mg, 0.288 mmol) in acetonitrile (1.2 mL) at 0° C. was added formalin (0.15 mL). The ice bath was removed and stirring continued for 1 h, occasionally treating with a small drop of acetic acid to keep the pH slightly less than 7. The reaction was concentrated, dissolved in methanol, and loaded onto an SCX cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The crude product was eluted with 2M ammonia in methanol and concentrated. The product was purified by column chromatography (5%-->10% MeOH/DCM) to give 15 mg (56%) as a colorless film. 1H-NMR (CD3OD, 300 MHz) δ 7.84 (m, 3H), 7.08-7.27 (m, 4H), 4.69 (qAB, JAB=13.1 Hz, 2H), 4.01 (m, 1H), 3.93 (ddd, J=11.3, 5.2, 4.0 Hz, 1H), 3.80 (qAB, JAB=10.4 Hz, 2H), 2.88 (m, 1H), 2.68 (ddd, J=16.2, 3.7, 3.4 Hz, 1H), 2.50 (m, 1H), 2.22 (m, 1H), 2.18 (s, 6H), 2.00-2.12 (m, 2H); 13C-NMR (CD3OD, 126 MHz) δ 142.6, 137.3, 135.3, 131.7 (q, J=32.6 Hz), 129.0, 127.5, 126.9, 126.5, 125.6, 123.8 (q, J=272 Hz), 121.0, 78.3, 76.7, 71.7, 60.7, 54.1, 44.3, 35.2, 29.4. Mass spec.: 462.40 (MH)+. Accurate mass spec.: m/z 462.1882 [MH]+, Δ=3.1 ppm.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([CH:7]1[O:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[N:9]([CH:26]([CH3:28])[CH3:27])[C:8]1=[O:29])[OH:6])C.[OH-].[Na+].Cl>C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:10]2[N:9]([CH:26]([CH3:28])[CH3:27])[C:8](=[O:29])[CH:7]([CH:5]([OH:6])[C:4]([OH:30])=[O:3])[O:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:11]=2[CH:21]=1
Reactant: CCOC(=O)C(O)C1OC(c2ccccc2Cl)c2cc(Cl)ccc2N(C(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1C(=O)C(C(O)C(=O)O)OC(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
A mixture (4.5 g) of (3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid ethyl ester and (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid ethyl ester obtained in Example 2 was dissolved in ethanol (50 ml). To the solution was added 1N sodium hydroxide (30 ml), and mixture was stirred for 30 minutes at room temperature. To the resultant mixture was added 1N hydrochloric acid (100 ml) to make the solution acid, which was extracted with ethyl acetate (200 ml). The extract solution was washed with water, dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was crystallized from hexane-ethyl acetate to give a mixture (3.3 g) of (3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid and (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid. This mixture was recrystallized twice from hexane-ethanol to give (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid (0.94 g) as plates, m.p. 226°-230° C. (decomp.).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O:33][C:34]([C@H:36]1[CH2:40][C@@H:39](O)[CH2:38][N:37]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:35].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O>[C:45]([O:44][C:42]([N:37]1[CH2:38][C@@H:39]([O:3][S:2]([CH3:1])(=[O:5])=[O:4])[CH2:40][C@@H:36]1[C:34]([OH:35])=[O:33])=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CS(=O)(=O)O
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1C(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 104.5 %

Procedure:
To a suspension of 6.7 ml (103.3 mmol) methanesulfonic acid, 14.4 ml (103.3 mmol) triethylamine and 28.8 g (107.6 mmol) triphenylphosphine in 280 ml toluene was added a suspension of 21.12 g (86.12 mmol) (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [prepared according to “Synthesis of macrocyclic dilactones by cyclization of sulfonium salts”. T. Nakamura, H. Matsuyama, N. Kamigata, M. Iyoda, J. Org. Chem. (1992), 57(14), 3783-9] in 180 ml toluene. After adding 21.6 ml (112 mmol) of diisopropyl azodicaboxylate (exothermic!) the solution was heated for 2.5 h at 80° C. and was stirred at RT for 1 day. 300 ml water was added at RT and extracted with ethylacetate (3×300 ml). The organic phase was washed with aqueous 1M KHSO4 (2×100 ml), brine (2×150 ml), dried over Na2SO4 and evaporated to give 27.85 g (2R,4S)-4-Methanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as crude product which was dissolved in THF and treated with LiOH according to 5.2.to give (2R,4S)-4-Methanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]Cl.[SH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O.[OH-].[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCS
Reactant: ClSc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCSSc1ccccn1

Procedure:
2.4 g of 2-pyridine sulfenyl chloride are dissolved in 40 ml of methylene chloride, and a solution of 1.75 g of 3-mercaptopropionic acid in 10 ml of methylene chloride is added slowly, whilst stirring and cooling with an ice bath. When the addition is complete, the mixture is stirred at ambient temperature for 15 hours. 50 ml of water are added and the pH is brought to 4.5 by adding 1 N sodium hydroxide solution. The organic phase is separated off and dried over sodium sulphate and the solvent is evaporated off to dryness. An oily product remains and this crystallises (1.8 g). It is purified by dissolution in 16.8 ml of a 0.5 M aqueous solution of sodium bicarbonate. Activated charcoal is added, the solution is filtered and the expected product is then precipitated by adding concentrated acetic acid (0.5 ml) so as to bring the pH to between 3 and 3.5. The precipitate is filtered off and dried under high vacuum and a solid (1.3 g), melting point (capillary method): 62°-64° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH2:10][CH2:11]Cl)=[CH:4][C:3]=1[Cl:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[Cl:14])[NH:8][C:9](=[O:13])[CH2:10][CH2:11]2
Reactant: O=C(CCCl)Nc1ccc(Br)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with N-(4-bromo-3-chloro-phenyl)-3-chloro-propionamide (1.0 g, 3.36 mmol) and aluminium chloride (0.67 g, 5.04 mmol). In a pre-heated oil bath, the flask was heated at 135˜140° C. for 2 hours. After cooling to room temperature, the reaction mixture was treated slowly with ice-water, then extracted with EtOAc. The organic layer was washed with water and brine in sequence and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by recrystallization from EtOAc (2 mL) which gave title compound (0.44 g, 50%) as a solid. MS: 260.0 (M+H+)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.CCOCC>C(O)(=O)C>[Br-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N)cc1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.50 g of p-(dimethylamino)benzaldehyde are added to a solution of 3.7 g of 1-amino-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide in 25 ml of glacial acetic acid. The mixture is stirred at room temperature for 15 hours. Then, 20 ml of ether are added thereto and, after an additional 3 hours, the product is removed by filtration. After recrystallization from ethanol/ether, there is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide of melting point 241°.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:22]([N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1)[CH3:23]>>[CH2:22]([N:24]1[CH:28]=[C:27]([NH:29][C:2]2[N:21]=[C:5]3[C:6]([O:10][C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:26]=[N:25]1)[CH3:23]
Reactant: CCn1cc(N)cn1
Reactant: CS(=O)(=O)c1ccc(Oc2cccn3nc(Cl)nc23)cc1
Product: CCn1cc(Nc2nc3c(Oc4ccc(S(C)(=O)=O)cc4)cccn3n2)cn1

Procedure:
A well stirred mixture of 2-amino-[1,2,4]triazolo[1,5-a]pyridine-8-ol (0.300 g, 2.00 mmol), 1-fluoro-4-methanesulfonyl-benzene (0.418 g, 2.40 mmol), N,N-dimethylacetamide (2 mL) and potassium tert-butoxide (0.448 g, 4.00 mmol) was heated at 130° C. for 18 h under an argon atmosphere. The reaction mixture was evaporated in vacuo and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to furnish a crude product. The crude product was purified by preparative Gilson HPLC method to yield a pure product, which was triturated from a mixture of dichloromethane, methanol, ether and hexane. 8-(4-Methanesulfonyl-phenoxy)-[1,2,4-triazolo[1,5-a]pyridin-2-ylamine was isolated as a white solid (125 mg, 20%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.53 (d, J=6.56 Hz, 1H), 7.87 (d, J=8.77 Hz, 2H), 7.36 (d, J=7.73 Hz, 1H), 7.15 (d, J=8.76 Hz, 2H), 6.92 (t, J=7.28 Hz, 1H), 6.13 (s, 1H), 3.19 (s, 3H). MS=305 (MH)+. 211b) 2-Chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine was prepared in a manner analogous to Example 68a. Product was isolated as a yellow solid (0.455 g, 80%). MP=202-204° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.44 (d, J=6.77 Hz, 1H), 7.98 (d, J=8.08 Hz, 2H), 7.21 (t, J=7.76 Hz, 3H), 7.08 (t, J=7.52 Hz, 1H), 3.09 (s, 3H). MS=324 (MH)+. 211c) (1-Ethyl-1H-pyrazol-4-yl)-[8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (0.065 g, 0.20 mmol) and 1-ethyl-1H-pyrazol-4-ylamine (0.029 g, 0.26 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (45 mg, 56%). MP=183-185° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.27 (s, 1H), 8.67 (d, J=6.51 Hz, 1H), 7.89 (d, J=7.72 Hz, 2H), 7.68 (s, 1H), 7.45 (d, J=7.74 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J=7.29 Hz, 2H), 7.00 (t, J=7.29 Hz, 1H), 4.055 (q, J=7.18 Hz, 2H), 3.20 (s, 3H), 1.32 (t, J=7.06 Hz, 3H). MS=399 (MH)+.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].S([O-])([O-])(=O)=O.[Mg+2].[CH3:13][C:14]([CH3:16])=O>>[CH3:13][C:14]1([CH3:16])[O:6][CH:3]([CH2:2][Br:1])[CH2:4][O:5]1
Reactant: CC(C)=O
Reactant: OCC(O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC1(C)OCC(CBr)O1

Procedure:
An acetone solution of bromomethyl ethylene glycol is refluxed for 24 hours in the presence of anhydrous magnesium sulfate. The cooled reaction mixture is filtered and the solvent is removed to provide a residual crude product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[N:9]=[C:8]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]2)(=[O:3])[CH3:2].Cl.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:40](=[O:47])[C:41]3[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=3)[CH:16]=1)[N:9]=[C:8]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccc2nc(-c3cccc(NC(=O)c4cccnc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
A suspension of tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.50 g, 0.98 mmol), nicotinoyl chloride hydrochloride (0.224 g, 1.26 mmol) and DIEA (0.45 g, 3.48 mmol) in CH2Cl2 (15 mL) was stirred at RT for 7 h. The volatiles were removed in vacuo and the residue was purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the product tert-butyl 5-(6-acetoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.374 g, 0.608 mmol, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13]C=2C)[N:4]=1.C(OCC)(=[O:23])C.O=[O+][O-]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:13])=[O:23])[N:4]=1
Reactant: COc1cc(OC)nc(-c2c(C)[nH]c3ccccc23)n1
Reactant: CCOC(C)=O
Agent: O=[O+][O-]
Solvent: O
Product: COc1cc(OC)nc(C(=O)c2ccccc2N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
In a reactor were placed 0.60 g (22 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole and 20 ml of ethyl acetate. Thereinto was blown ozone at 0° C. to 10° C. for 4 hours. Thin-layer chromatography was conducted to confirm the disappearance of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole and complete a reaction. Then, the reaction mixture was heated to room temperature and concentrated. To the concentrate were added 20 ml of methanol and 5 ml of 6 N hydrochloric acid, and refluxing was made for 1 hour with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature. 100 ml of water was added. The mixture was made alkaline with an aqueous sodium hydroxide solution, and extraction was made with ethyl acetate. The organic layer was concentrated. The concentrate was subjected to column chromatography separation to obtain 0.26 g (10 m moles) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)aniline. Yield: 46%