Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][C@H:18]([CH3:22])[C:19](O)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)([Cl:27])=O.CN(C=O)C>CCOCC>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][C@H:18]([CH3:22])[C:19]([Cl:27])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[C@@H](Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.06 g (2.94 mmol) of (R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid in 5 ml of dry ether under a nitrogen atmosphere and cooled to 0° is added 400 μl (5.50 mmol, 0.66 g) of thionyl chloride and 50 μl of DMF. After 5 hours at 0°, the reaction is stirred at RT overnight. The ether solution of acid chloride is then removed from the oily residue, and the ether and excess thionyl chloride are removed by rotoevaporation to give (R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid chloride.
Reaction SMILES: [S:1]=[C:2]1[NH:10][C:9]2[NH:8][CH:7]=[N:6][C:5]=2[C:4](=S)[NH:3]1.O.[NH2:13][NH2:14]>>[NH:13]([C:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[NH:10][C:2](=[S:1])[N:3]=1)[NH2:14]
Reactant: NN
Reactant: S=c1[nH]c(=S)c2nc[nH]c2[nH]1
Solvent: O
Product: NNc1nc(=S)[nH]c2[nH]cnc12
Temperature: 120 °C
Yield: 61 %

Procedure:
2,6-Dithioxo-1,2,3,6-tetrahydro-9H-purine (0.5 g, 2.7 mmol) was added to 80% hydrazine hydrate (5 ml), and the mixture was stirred with heat for 10 minutes at 120° C. After completion of reaction, crystals that precipitated were collected by filtration, and washed with water. The crystals were recrystallized from water to obtain 0.30 g (yield 61%) of colorless powdery crystals (m.p.=292° C. (decomposed)).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21](F)=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[CH:14][C:13]=2[F:30])[CH2:8]1>CO>[NH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([O:2][CH3:1])=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[CH:14][C:13]=2[F:30])[CH2:8]1
Reactant: C[O-]
Reactant: NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(N2CCC(CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 86 h

Procedure:
To a solution of sodium methoxide prepare from sodium (0.2 g) and absolute methanol (9 ml) was added 7-(3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g) and the mixture in sealed tube was stirred for 86 hours at 140° to 150° C. and then concentrated. Small amount of water was added to the residue, and the solution was adjusted pH 7 with acetic acid and then concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from methanol to give the title compound (40 mg) as pale yellow prisms, mp 225°-228.5° C. (decompd.).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([P:14](=[O:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=1.[H-].[Na+].Cl[C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]=[C:33]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:32]=1>CN(C=O)C>[C:43]1([C:33]2[N:34]=[C:35]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:36]=[C:31]([N:12]3[C:13]4[CH:1]=[CH:2][C:3]([P:14](=[O:27])([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:32]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccc2[nH]c3ccccc3c2c1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(c1)c1ccccc1n2-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
9H-3-carbazolyl(diphenyl)phosphine oxide (8 g), prepared as above, was dissolved in 120 ml of dry N,N′-dimethylformamide under nitrogen. 1.2 g of sodium hydride was added and stirred at room temperature for 1 h. A solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (U-1, 7.0 g) in dry N,N′-dimethylformamide (50 ml) was then added to the reaction mixture. The reaction was further allowed to stir for 24 h. The product was precipitated by pouring the reaction mixture into water. The solid thus obtained was then washed with methanol, followed by n-hexane and dried under vacuum to obtain 9 g of 9-(4,6-diphenyl-1,3,5-triazin-2-yl)-9H-3-carbazolyl(diphenyl)phosphine oxide, compound 8-8 (71%).
Reaction SMILES: [NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([F:23])[C:3]=1[F:24]>OS(O)(=O)=O.O.CC(O)=O>[NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([F:23])[C:3]=1[F:24]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OC[C@@H]2CF
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](CF)CO2
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A suspension of ethyl (3R)-8-amino-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (270 mg, 0.789 mmol) in a mixture of H2SO4—H2O—AcOH (1:5:6, 3 mL) was heated under reflux for 1 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were washed with water, and dried in vacuo to give (3R)-8-amino-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (237 mg, 96%) as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[Mg].[Cl-].[NH4+].C([O:22][CH2:23][CH3:24])C>O1CCCC1.O>[OH:22][CH:23]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1)[CH2:24][CH2:4][CH2:3][CH2:2][CH2:16][CH2:6][CH2:7][CH2:10][CH2:11][CH3:12]
Reactant: Brc1ccc2occ(-c3ccccc3)c2c1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCC(O)c1ccc2occ(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.5 g. (0.02 mole) of 5-bromo-3-phenylbenzofuran in tetrahydrofuran is added 0.5 g. (0.02 mole) of magnesium, and the mixture is heated at its reflux temperature for three hours. After cooling to 0° C., 3.4 g. of undecyl aldehyde is added. After stirring for 30 minutes at room temperature, the solution is added to ammonium chloride solution. Evaporation provides a residue which is mixed with diethyl ether and water. The ether layer is separated, washed with saturated sodium chloride solution, dried and evaporated. The resulting oil is dissolved in carbon tetrachloride and eluted from a silica gel column with carbon tetrachloride, then with dichloromethane. The later fractions are evaporated to provide 5-(α-hydroxyundecyl)-3-phenylbenzofuran which is dissolved in dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].Cl.CN(C)CCCN=C=NCC.O[CH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>O1CCCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:47][CH2:48][CH2:49][N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: OCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCCCN5CCOCC5)c[nH]4)c3)cc2)c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 63 mg, 0.33 mmol) in 10 ml of anhydrous tetrahydrofuran were added N-(3-hydroxypropyl)morpholine (64 mg, 0.44 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was heated at 60° C. for 3 hours, cooled to room temperature and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to afford 3-morpholin-4-ylpropyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 72 mg, 56%.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)/C=C/C(O)=O.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH:37]1[CH2:46][CH:47]1[CH2:51][NH:50][CH:49]=[N:48]1>C1C=CC=CC=1>[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH:37]1[CH2:46][CH:47]1[CH2:51][N:50]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:49]=[N:48]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1=NC(CC2CCc3ccccc3C2)CN1
Agent: O=C(O)/C=C/C(=O)O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C1=NC(CC2CCc3ccccc3C2)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
1.25 ml (9 mmol) of triethylamine and 2.36 g (8.50 mmol) of trityl chloride are added, in succession, at 20° C., to a solution of the compound obtained in Example 16 (Step 4) in the form of the free amine (1.80 g, 8.40 mmol) in 50 ml of benzene, under nitrogen. After stirring for 15 hours at 20° C., the mixture is washed with H2O, and the organic phase is dried and concentrated in vacuo to yield an oily residue. Chromatography on a chiral column, eluting with a solution of triethylamine in toluene (0.5%), allows the 4 isomers to be separated in the form of white solids.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:16]([NH:15][CH2:14][C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:17]
Reactant: CCNCC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCNCC1(O)CCNC1

Procedure:
10 g (42.7 mmol) of 1-benzyl-3-ethylaminomethyl-3-hydroxypyrrolidine in 60 ml of methanol are hydrogenated using 2 g of palladium/active carbon (10%) at 92°C. and 107 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Temperature: 120 °C

Procedure:
2,6-dichloro-9-isopropylpurine (0.019 g, 0.081 mmol) was dissolved in butanol (0.5 ml) and aniline (0.044 ml, 0.244 mmol) was added. The reaction mixture was heated to 120° C. for 10 hr, cooled, diluted with EtOAc and washed 3 times with water. The mixture was dried over MgSO4 and concentrated to an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.CO[C:33]1C=C(S(Cl)(=O)=O)C=C[CH:38]=1>>[CH2:33]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:10])=[O:11])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:38]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cccc(S(=O)(=O)Nc2cccc(C(=O)Nc3ccc(C(=O)O)cc3)c2)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(OC)c3)c2)cc1

Procedure:
4-[3-(3-Methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=425.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3-methoxy-benzenesulfonyl chloride and yielded 4-[3-(3-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[NH:25][C:24](=[O:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:27].[C:30]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[N:25]([CH3:30])[C:24](=[O:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:27]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)Cn1c(Cn2[nH]c(=O)c3ccccc3c2=O)cc2cnc(C#N)nc21
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2ccccc2c(=O)n1Cc1cc2cnc(C#N)nc2n1CC(C)(C)C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of 338 mg (1.3 mmoles) of phthalhydrazide in 20 ml of DMF, 252 mg (1.83 mmoles) of K2CO3 and 400 mg (1.30 mmoles) of 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:2) give 412 mg of desired 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 70% yield. The obtained product is treated with MeJ under the same conditionto give N-methylated compound. To a solution of 295 mg (0.76 mmoles) of 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 20 ml of DMF, 0.066 ml (1.06 mmoles) of MeJ and 168 mg (1.22 mmoles) of K2CO3 are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:4) give 238 mg of 7-(2,2-Dimethyl-propyl)-6-(3-methyl-1,4dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:26](OC(C)C)(C)C>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)OC(C)C
Reactant: COC(=O)C(c1cc2c(cc1Cl)OCO2)c1c[nH]c2cc(Br)ccc12
Product: COC(=O)C(c1cc2c(cc1Cl)OCO2)c1cn(C)c2cc(Br)ccc12

Procedure:
The subtitle compound was prepared following the procedure of Example 92(d), using methyl 2-(6-bromo-1H-3-indolyl)-2-(6-chloro-1,3-benzodioxol-5-yl)acetate from step (c). m.p. 183-185° C. from diisopropyl ether.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[NH2:27].Cl.[N:29]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:6]=1[NH:27][N:29]=[C:13]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=N[O-]
Reactant: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c(N)c(OCCCl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OCCCl)c2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-methoxy-6-(naphthalene-1-sulfonylmethyl)-phenylamine (1.0 g, 2.46 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.17 g, 2.6 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.0 g, 2.39 mmoles).
Reaction SMILES: C[CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:3]1=[N:13][OH:14].[ClH:15]>C(OC)(C)(C)C>[Cl:15][CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:3]1=[N:13][OH:14]
Reactant: Cl
Reactant: CC(C)OC(=O)C1SCC(C)C1=NO
Solvent: COC(C)(C)C
Product: CC(C)OC(=O)C1SCC(Cl)C1=NO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
334 g (1.54 mol) of i-propyl 4-methyl-3-hydroximino-tetrahydrothiophene-2-carboxylate are dissolved in 5 litres of methyl tert-butyl ether and cooled using an ice bath. Hydrogen chloride is then—after the ice bath had been removed—introduced with stirring for two hours. The mixture is subsequently concentrated using water pump vacuum and the amorphous residue is crystallized from acetone.
Reaction SMILES: [Cl-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:34][C:35]1[C:40]([C:41]([C:43]2[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=2)=O)=[CH:39][C:38]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[C:52]([O:58][CH3:59])[CH:51]=2)=[CH:37][N:36]=1>C1COCC1>[CH3:59][O:58][C:52]1[CH:51]=[C:50]([C:38]2[CH:39]=[C:40]3[C:41]([C:43]4[CH:48]=[CH:47][C:46]([NH2:49])=[N:45][CH:44]=4)=[CH:2][NH:34][C:35]3=[N:36][CH:37]=2)[CH:55]=[CH:54][C:53]=1[O:56][CH3:57]
Reactant: COc1ccc(-c2cnc(N)c(C(=O)c3ccc(N)nc3)c2)cc1OC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccc(N)nc4)c3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (166 mg, 0.485 mmol) in THF (1 ml) at 0° C. under nitrogen was added potassium bis(trimethylsilyl)amide (97 mg, 0.485 mmol). The mixture was stirred at room temperature for 30 min, then it was added to [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-(6-amino-pyridin-3-yl)-methanone (34 mg, 0.097 mmol) in one portion. The reaction mixture was stirred for 2 hours, then quenched with wet methanol and concentrated in vacuo. The crude was diluted with 2 ml of 1,4-dioxane and treated with 0.1 ml of aqueous 70% perchloric acid. The mixture was stirred at 80° C. for 19 hours, diluted with THF/methanol (1:1), and treated with 2.0 g of PS-trisamine (Argonaut Technologies, 4 equivalents per equivalent of acid used) for 30 minutes. The resin was filtered off and washed with THF-MeOH (1:1). Purification was accomplished by flash chromatography on silica gel with a gradient, of methanol/dichloromethane afforded 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-ylamine as a yellow solid (9.7 mg, 29% yield). 1H NMR (DMSO-d6): δ 11.8 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.77 (dd, J=2.0, 10.0 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.24 (dd, J=2.0, 7.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.90 (broad s, 2H), 3.86 (s, 3H), 3.79 (s, 3H). HPLC/MS m/z 347.1 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](Cl)[C:6]=2[CH:17]=1.[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][Mg]Br)[CH3:19].Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:23][CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:6]=2[CH:17]=1
Reactant: CCOCCC[Mg]Br
Reactant: Clc1ccc2c(c1)C(Cl)c1ccccc1C=C2
Agent: Cl
Solvent: CCOCC
Product: CCOCCCC1c2ccccc2C=Cc2ccc(Cl)cc21

Procedure:
3,5-Dichloro-5H-dibenzo[a,d]cycloheptene, dissolved in absolute ether, is added dropwise with stirring to a solution containing one equivalent of 3-ethoxypropylmagnesium bromide in ether. The mixture is stirred at room temperature for 1 hour, then at reflux for 2 hours. The mixture then is cooled, treated with dilute hydrochloric acid and the ether separated, washed with water and dried. The product is isolated by evaporation of the ether.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]1[CH2:40][C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:38]([CH:47]=O)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:29]([O:33][C:34]([N:36]1[CH2:40][C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:38]([CH2:47][N:16]2[CH2:15][CH2:14][C:11]3([C:10](=[O:19])[N:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)[CH2:18][CH2:17]2)[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Reactant: COc1ccc(CN2CCC3(CCNCC3)C2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC3(CCN(C[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4c4ccccc4)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.41 g of 2-(4-methoxy-benzyl)-2,8-diaza-spiro[4.5]decan-1-one hydrochloride (12.3 mmol) in dichloromethane (50 mL) was added triethylamine (1.71 mL, 12.3 mmol) followed by 3.85 g of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (12.3 mmol) in dichloromethane (75 mL) and stirred for 1 h at room temperature. Sodium triacetoxyborohydride (3.91 g, 18.4 mmol) was then added and the reaction mixture stirred overnight at room temperature.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:11]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: Cc1ccc2cccnc2c1NS(=O)(=O)c1ccccc1
Yield: 66.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 7-methyl-8-aminoquinoline (200 mg, 1.26 mmol), benzenesulfonyl chloride (260 mg, 1.5 mmol) and DMAP (cat.) gave the title compound (250 mg, 67%) after purification by column chromatography with DCM as the eluent.