Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>ClCCl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=1)=[O:10])=[O:2]
Reactant: COc1ccc(C=O)cc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Publicly known [e.g. E. J. Wayne et al, J. Chem. Soc., 1022(1922)] 5-formyl-2-methoxybenzoic acid (4.05 g, 22.5 mmol) was dissolved in 80 ml of dichloromethane, which was cooled with ice. Triethylamine (7.94 ml, 56.2 mmol) was added under stirring. Next, ethyl chlorocarbonate (2.44 ml, 24.8 mmol) was added and, after stirring for 10 minutes, 4-(trifluoromethyl)benzylamine (3.31 ml, 22.5 mmol) was added dropwise, which was allowed to stand overnight. After washed with water, the reaction mixture was dried over anhydrous sodium sulfate and concentrated. Water was added to the residue, which was made acidic with dilute hydrochloric acid. Then, the precipitates were filtered and dried to quantitatively obtain the title compound as milky white crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C#N)cc1Cl
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 3-chloro-4-methoxybenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 3-chloro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: CC1C=CC(N2C3C(=CC=CC=3)C=C2)=CC=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.[F:45][C:46]1[CH:51]=[CH:50][C:49](I)=[CH:48][CH:47]=1>>[F:45][C:46]1[CH:51]=[CH:50][C:49]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([C:33]5[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH:36]=[CH:37][CH:38]=5)[CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:48][CH:47]=1
Reactant: Fc1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Agent: Cc1ccc(-n2ccc3ccccc32)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccc(F)cc4)c3)CC2)c1
Yield: 44.7 %

Procedure:
According to the procedure used for the synthesis of 1-(4-methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100 mmol) and 1-fluoro-4-iodobenzene (44.4 mg, 0.200 mmol) gave the desired product (21 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 7.71-6.60 (m, 14H), 3.69 (s, 2H), 3.19-2.99 (m, 2H), 2.62-2.41 (m, 2H), 2.22-2.07 (m, 2H), 1.94-1.70 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 470.2 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][CH3:11])[NH:7][CH:8]=1.CN(C)C=O.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[N:19]=1>O>[CH3:28][O:27][C:20]1[N:19]=[C:18]([N:7]2[CH:8]=[C:4]([CH3:3])[N:5]=[C:6]2[CH2:9][CH2:10][CH3:11])[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CCCc1nc(C)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(C)cn1-c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a suspension prepared of 20.0 g KOH (solid), 25.8 g 4-methyl-2-propyl imidazole and 130 ml dimethyl formamide were added 38.0 g 2-chloro-6-methoxy-3-nitro pyridine in small amounts at a reaction temperature of 5° C. The reaction mixture was stirred for 75 minutes at room temperature. Then the reaction mixture was poured in 600 ml water. The mixture was further stirred for 1 hr. The desired product precipitated during this time. The resulting solid was collected by filtration, washed with 100 ml water for 3 times and dried in a dry box with vacuum (40° C.).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:17]1[CH:39]=[CH:38][C:20]([CH2:21][N:22]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:39]=[CH:38][C:20]([CH2:21][N:22]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(I)cc1)S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCCCCCN(Cc1ccc(-c2ccccc2)cc1)S(C)(=O)=O
Yield: 80.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.09 mmol), aqueous Na2CO3 (0.9 mL, 1M), and phenyl boronic acid (216 mg, 1.77 mmol) were added to a solution of ethyl 7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (415 mg, 0.89 mmol) in toluene (37 mL) and EtOH (7 mL). The reaction mixture was heated at reflux for 3 h. The solution was diluted with EtOAc and was washed with water (2×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (10% EtOAc/hexanes to 30% EtOAC/hexanes) provided the title compound of Step A (298 mg). 1H NMR (400 MHz, CDCl3) δ7.62-7.30 (m, 4H), 4.41 (s, 2H), 4.12 (q, 2H), 3.20 (t, 2H), 2.82 (s, 3H), 2.23 (t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 418.3 (M+).
Reaction SMILES: [CH2:1]([CH:10]1[C:15](=O)[CH2:14][CH2:13][S:12](=[O:18])(=[O:17])[CH2:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH3:21].C(O)(=O)C.Cl>O>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:25]1[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:10]2[CH2:11][S:12](=[O:18])(=[O:17])[CH2:13][CH2:14][C:15]1=2
Reactant: CN(C)CCCN
Reactant: O=C(CC1CS(=O)(=O)CCC1=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCCn1c(-c2ccccc2)cc2c1CCS(=O)(=O)C2

Procedure:
A solution of 2.0 g (0.0075 mole) of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one-1,1-dioxide, 0.85 g of dimethylaminopropylamine and 30 ml. of acetic acid is heated under reflux for 5 hours. The reaction solution is cooled, diluted with water, adjusted to a pH of 1 with hydrochloric acid, and then washed with ether. The solution is made basic with sodium bicarbonate and extracted with ether. The ether extract is dried and concentrated to a solid. The solid is recrystallized from 2-propanol to give off-white needles of 1-(3-dimethylaminopropyl)-2-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole-5,5-dioxide, m.p. 123° to 125°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[CH2:54][CH2:53][N:52]([S:55]([CH3:58])(=[O:57])=[O:56])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([N:49]5[CH2:54][CH2:53][N:52]([S:55]([CH3:58])(=[O:57])=[O:56])[CH2:51][CH2:50]5)[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 0 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (1.00 g, 2.2 mmol), 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.80 g, 2.2 mmol), p-toluenesulfonic acid (0.99 g, 5.2 mmol) and iPrOH (20 mL) was heated in the microwave at 175° C. for 20 min. LCMS indicated the reaction had proceeded to completion and the reaction mixture was concentrated onto silica gel. Flash chromatography afforded the title compound (1.1 μg, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.40 (bs, 1H), 8.45 (s, 1H), 8.33-8.31 (m, 1H), 8.19 (d, J=5.2 Hz, 1H), 8.07-8.03 (m, 1H), 7.83-7.80 (m, 1H), 7.74-7.71 (m, 1H), 7.60 (at, J=7.7 Hz, 1H), 7.48-7.35 (m, 3H), 7.23-7.17 (m, 2H), 7.01-6.95 (m, 1H), 6.67 (d, J=2.5 Hz, 1H), 6.50-6.44 (m, 2H), 3.79 (s, 3H), 3.76-3.70 (m, 2H), 3.11-3.06 (m, 4H), 2.85 (s, 3H), 2.71-2.63 (m, 2H), 2.62-2.57 (m, 4H), 2.46-2.36 (m, 2H), 1.87-1.79 (m, 2H), 1.60-1.47 (m, 2H). MS (ES+, m/z) 794 (M+1).
Reaction SMILES: N1C2C(=CC(O[C:11]3[C:20]4[C:15](=[CH:16][C:17](OCCCN5CCNCC5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=CN=2)C=C1.ICC(N)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[CH:11]2
Reactant: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCNCC1
Agent: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc2ncncc2c1
Temperature: 25 °C
Yield: 193.5 %

Procedure:
A mixture of 4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (87 mg, 0.2 mmol), (prepared as described for the starting material in Example 34), iodoacetamide (41 mg, 0.22 mmol) and N,N-diisopropylethylamine (26 mg, 0.22 mmol) in acetonitrile (5 ml) was stirred at reflux for 1 hour and allowed to cool to ambient temperature. The crude reaction mixture was loaded onto a silica column and eluted using methylene chloride/methanol (saturated with ammonia) (92/8) solvent. The relevant fractions were combined and evaporated under vacuum to give a residue which was triturated with acetone, filtered and dried to give 4-(7-azaindol-5-yloxy)-7-[3-(4-carbamoylmethyl)piperazin-1-yl)propoxy]-6-methoxyquinazoline (62 mg, 63%).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>C([O-])(=O)C>[C:25]1([CH2:31][C:32]([NH:1][CH:2]2[C:23](=[O:24])[N:4]3[C:5]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=4)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12

Procedure:
For example, p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate is reacted with phenylacetyl chloride in cold aqueous acetate containing sodium bicarbonate to provide p-nitrobenzyl 7-phenylacetamido-3-chloro-3-cephem-4-carboxylate.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:18][C:17]=1[F:36])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:38][C:39]1[C:44](B(O)O)=[CH:43][CH:42]=[CH:41][N:40]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:20]1[C:19]([O:23][C:24]2[C:29]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[CH:28][C:27]([C:44]3[C:39]([F:38])=[N:40][CH:41]=[CH:42][CH:43]=3)=[N:26][CH:25]=2)=[CH:18][C:17]([F:36])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2ccoc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccnc3F)cc2-c2ccoc2)cc1F
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
10 mg of tert-butyl((5-chloro-4-((6-chloro-4-(furan-3-yl)pyridin-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 1,4-dioxane/H2O=1:1 (0.38 mL), and 3.5 mg of (2-fluoropyridin-3-yl)boronic acid, 0.65 mg (3 mol %) of Pd(PPh3)4 and 5.96 mg of Na2CO3 were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, 1,4-dioxane was removed by concentrating under reduced pressure. After extracting with ethyl acetate, the extract was treated with MgSO4, and concentrated under reduced pressure. The residue was separated by PLC (developing solvent, EA:n-Hex=1:1) to obtain 6.7 mg (72% yield) of the title compound.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1([OH:16])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)CCC.FC(F)(F)C(O)=O.[NH2:25][NH2:26]>C(Cl)Cl.CO>[OH:16][C:8]1([CH2:7][C:6]([NH:25][NH2:26])=[O:5])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: NN
Reactant: CCCCOC(=O)CC1(O)CN2CCC1CC2
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.5 g of the compound of step (a) in 15 ml of methylene chloride was added trifluoroacetic acid (39 ml) and the mixture was stirred at ambient temperature for three hours. The mixture was then concentrated in vacuo. The residue was dissolved in methanol (30 ml) and 18M H2SO4 (3 ml) was added and the mixture was stirred overnight. The mixture was then poured into a solution of sodium carbonate in water, extracted three times with chloroform, dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. The solid was dissolved in methanol (10 ml) and hydrazine (2 ml) was added to this solution and the mixture was heated to reflux for one hour. The mixture was then concentrated in vacuo. The resulting solid was suspended in toluene (50 ml) and heated to reflux in an apparatus equipped with a Dean-Stark trap for two hours. The reaction mixture was then allowed to cool, and the product was filtered off to give 1.82 g of the subtitle compound as a tan solid.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[O:19]=[S:20]1(=[O:34])[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>>[O:34]=[S:20]1(=[O:19])[CH2:21][CH2:22][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:29][CH:28]=2)[CH2:24][CH2:25]1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Product: O=S1(=O)CCN(Cc2ccc(Nc3ncc4ccc(-c5cccnc5)n4n3)cc2)CC1

Procedure:
[4-(1,1-Dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was prepared from 2-methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine and 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine in an analogous manner to Example 1049. Product isolated as an orange foam (19 mg, 11%). LCMS (m/e) 435 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.30 (s, 1H), 8.76 (s, 1H), 8.62 (d, 1H, J=3.8 Hz), 8.49-8.42 (m, 1H), 7.59 (d, 2H, J=8.4 Hz), 7.42 (dd, 1H, J=8.0 and 4.8 MHz), 7.29 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=4.8 Hz), 6.95 (s, 1H), 6.88 (d, 1H, J=4.8 Hz), 3.62 (s, 2H), 3.10-3.03 (m, 4H), 3.02-2.96 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI.CN([CH:25]=[O:26])C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([O:26][CH3:25])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Product: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To the solution of 2-bromoterephthalic acid (CIV) (5.0 g, 20.40 mmol) in DMF was added K2CO3 (7.9 g, 57.13 mmol) and CH3I (3.56 mL, 57.13 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with 1 N aqueous HCl, 1 M aqueous K2CO3, 10% aqueous Na2S2O3, brine, dried over anhydrous MgSO4, and concentrated under vacuum to give dimethyl 2-bromoterephthalate (CV) (4.82 g, 17.65 mmol, 99% purity, 80% yield). ESIMS found for C10H9BrO4 m/z 275.2 (M+2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 10 g of 4-hydroxybenzoic acid in 100 ml of N,N-dimethylformamide were added 29.1 g of 4-chlorobenzyl chloride and 25 g of potassium carbonate. The mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was treated with ethyl acetate-water. The resulting ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The resulting residue was washed with n-hexane, then collected by filtration, and suspended in 50 ml of ethanol. To the suspension was added 100 ml of a 2N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 4 days and then neutralized with concentrated hydrochloric acid. The resulting crystals were collected by filtration and recrystallized from chloroform to obtain 16.7 g of 4-(4-chlorobenzyloxy)benzoic acid.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH2:15]([NH:17][CH3:18])[CH3:16]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([N:17]([CH2:15][CH3:16])[CH3:18])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Reactant: CCNC
Product: CCN(C)C1=NS(=O)(=O)c2cc(Cl)ccc2N1

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (753 mg; 3 mmol) and N-ethyl-N-methylamine (708 mg; 12 mmol) and with the use of same procedure as in example 21 650 mg (79%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.4 (s, 1H, NH), 7.69 (d, 1H, H-8), 7.61 (dd, 1H, H-6), 7.55 (d, 1H, H-5), 3.5 (q, 2H, CH2), 3.09 (s, 3H, CH3), 1.10 (t, 3H, CH3); 13C-NMR (DMSO-d6) ppm; 150.21, 134.69, 131.81, 127.27, 123.98, 121.42, 119.54, 44.2, 34.69, 11.91. Analysis C10H12ClN3O2S requires C, 43.88; H, 4.42; N, 15.35; (found C, 43.52; H 4.55; N, 15.30).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13].O>CN1C(=O)CCC1>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNC
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)c1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (1.0 eq) and dimethylamine (2 M in EtOH, 4.6 eq) in NMP were heated for 2 h at 100° C. The solution was then poured slowly into H2O. The filtrate that formed was filtered and dried to give 2-(dimethylamino)-5-nitropyridine.
Reaction SMILES: C(O[C:9](=[O:38])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([F:37])[CH:25]=1)C1C=CC=CC=1.F[C:40](F)(F)C(O)=O>C1(SC)C=CC=CC=1>[CH:34]1([NH:33][C:31](=[O:32])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:14]3[C:13]4[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([NH:10][C:9](=[O:38])[CH3:40])[CH:12]=4)[N:17]=[CH:16][CH:15]=3)=[CH:25][C:26]=2[F:37])[CH2:35][CH2:36]1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1NC(C)=O

Procedure:
{4-[4-(cyclopropylureido)-3-fluorophenoxy]-7-methoxyquinolin-6-yl}carbamic acid benzyl ester (11 mg) was heated and stirred in a mixture of trifluoroacetic acid (3 ml) and thioanisole (0.5 ml) at 60° C., in the same manner as Example 264, for debenzylation. The resulting amino compound was acetylated in the same manner as Example 265 to obtain the title compound (2 mg) as a solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](OS(C(F)(F)F)(=O)=O)(CC)(CC)CC.ClC(Cl)(Cl)C(=N)O[C@H:28]1[O:49][C@H:48]([CH2:50][O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:39]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:34]([O:35][CH2:36][CH:37]=[CH2:38])[C@H:29]1[O:30][C:31](=[O:33])[CH3:32].C(N(CC)CC)C>ClCCl>[C:31]([O:30][C@@H:29]1[C@@H:34]([O:35][CH2:36][CH:37]=[CH2:38])[C@H:39]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@@H:48]([CH2:50][O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[O:49][C@H:28]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: C=CCO[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: OCc1ccccc1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCO[C@@H]1[C@@H](OC(C)=O)[C@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 91 %

Procedure:
1.62 mL (3 eq.) of benzyl alcohol and 130 μL (0.1 eq.) of TESOTf are added to 3.07 g (1 eq.) of 2-O-acetyl-3-O-allyl-4,6-di-O-benzyl-α-D-gluco-pyranosyl trichloroacetimidate (M=586.5) in 25 mL of dichloromethane at 0° C. in the presence of 2.5 g of 4 Å molecular seives. After 1 hour of reaction at 0° C., the medium is neutralised with triethylamine, filtered and concentrated. Purification over silica gel [flash; eluent: toluene/ethyl acetate (98/2; v/v)] enables isolating 2.52 g of benzyl 2-O-acetyl-3-O-allyl-4,6-di-O-benzyl-β-D-glucopyranoside (M=532).