Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[OH:9][N:8]=[C:7]([Cl:15])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=1
Reactant: ON=Cc1cccc(OC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1cccc(OC(F)(F)F)c1
Yield: 83.2 %

Procedure:
In a similar manner as described in Preparation Example 9, by using dimethylformamide (240 mL), 3-(trifluoromethoxy)benzaldehydeoxime (20.0 g, 97.50 mmol) and N-chlorosuccinimide (14.32 g, 107.26 mmol), a pale yellow solid required compound (19.43 g, 81.10 mmol, 82%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 3-methylpiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.87 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M+H)+=445.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:24])([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=O)[C:15]3[C:14]([C:26]([O:28]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:32][NH:33][C:26](=[O:28])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[C:17]2([CH3:24])[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(C)(c1ncnn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ncnc1C1(C)c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Yield: 54 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg, 0.19 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (1 mL) was stirred under reflux overnight. The resulting solution was cooled and filtered, washed the cake by methanol (2 mL) to obtain a white solid, dried in vacuum at 55° C. to obtain the title compound (40 mg, yield 54%). LC-MS (ESI) m/z: 377 (M+1)+; 1H-NMR (400 MHz, DMSO-d) δ (ppm): 1.83 (s, 3H), 2.86 (s, 3H), 4.61 (s, 1H), 6.88-6.92 (m, 2H), 7.11-7.169 (t, J=8.8 Hz, 2H), 7.19-7.22 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.47-7.49 (m, 1H), 7.60-7.64 (t, J=8.0 Hz, 1H), 7.72 (s, 1H), 12.40 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:15][CH:14]=2)[C:5](=[O:31])[C:4]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[O:38][C:37]([CH3:43])([CH3:42])[CH2:36][CH:35]2[OH:44])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH3:43][C:37]1([CH3:42])[CH2:36][C:35](=[O:44])[C:34]2[C:39](=[CH:40][CH:41]=[C:32]([C:4]3[C:5](=[O:31])[N:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:25]5[NH:29][C:28](=[O:30])[O:27][N:26]=5)=[CH:15][CH:14]=4)[C:7]([CH2:9][CH2:10][CH3:11])=[N:8][C:3]=3[CH2:1][CH3:2])[CH:33]=2)[O:38]1
Reactant: CCCc1nc(CC)c(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(CC)c(-c2ccc3c(c2)C(=O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of 6-ethyl-5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one (0.78 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.84 g) in dichloromethane (8 mL) was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 81%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH3:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15](O)[CH:14]=1>>[Cl:7][C:15]1[CH:14]=[C:13]([CH3:12])[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=1
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
Add phosphorus oxychloride (0.6 mmol, 0.05 mL) and phosphorus pentachloride (0.6 mmol, 0.12 g) over 4-methyl-5-nitro-pyridin-2-ol (1.9 mmol, 0.3 g). Stir at 120° C. for 1.5 hours. Cool down, add ice-water and extract in CH2Cl2. Wash combined organic layers with saturated aq. sodium chloride solution. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 2-chloro-4-methyl-5-nitro-pyridine.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:34]=[CH:33][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=3)[S:17][C:13]=2[CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:35]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([CH3:35])[C:11]1[CH:34]=[CH:33][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=3)[S:17][C:13]=2[CH:12]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccc(NC(=O)OC(C)(C)C)cc3s2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccc(CNC(=O)OC(C)(C)C)nc3)sc2c1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
NaH (95%, 4.5 mg, 0.18 mmol) was added to a solution of tert-butyl (5-{6-[(tert-butoxycarbonyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)methylcarbamate (66 mg, 0.14 mmol) in DMF (2 mL). The mixture was cooled to 0° C. and MeI (10 μL, 0.16 mmol) was added. The reaction was stirred at rt on. Water was added and the mixture was extracted with EtOAc (3×) The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (Heptane/EtOAc gradient) gave the product (60 mg) as a white solid. MS m/z (M+H) 471.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:30]([O:32][C:33](=[O:46])[C@@H:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:46])[C@@H:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:10][CH2:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:38][CH:37]=1)[CH3:31]
Reactant: OCC=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccccc2)c2ccccc2)cc1)OCC
Yield: 67.4 %

Procedure:
Reaction of 3,3-diphenyl-prop-2-en-1-ol (210 mg, 1.0 mmol), tributylphosphine (303 mg, 1.50 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (250 mg, 1.05 mmol) and azodicarboxylic dipiperidide (378 mg, 1.50 mmol) in an identical manner to example 3 gave the title compound (290 mg, 67%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc2c(cc1OC1CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Yield: 86 %

Procedure:
A solution of 3-(7-isopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 13) Rt=2.104 min, 0.042 g, 0.098 mmol) in DCM (2 mL) and TFA (0.5 mL) was stirred at 25° C. for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-yloxy)-7-isopropyl-4(R)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (SFC (Table 1, Method 14), Rt=1.610 min, 0.036 g, 86%) as a pale yellow solid. LC/MS (Table 1, Method 5) Rt=2.077 min.; MS m/z: 331 [M+H]+.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1.[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].N>>[CH2:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:7]=[C:2]([NH:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNc1nc(N)nc(NCCCC)n1
Reactant: CCCCCCCCCCCCN
Agent: N
Product: CCCCCCCCCCCCNc1nc(NCCCC)nc(NCCCC)n1

Procedure:
The same procedures were repeated as in the N-substituted melamine (C1), except that n-dodecyl amine was employed in place of the aqueous ammonia to obtain 2,4-bis(monobutyl-amino)-6-(monododecylamino)-1,3,5-triazine which is in a solid-state.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:13])[C:8]=2[NH2:12])[CH:3]=1.[C:14]([O:18][C:19]([N:21]1[C@H:26]([C:27](O)=[O:28])[C@H:25]2[CH2:30][C@@H:22]1[CH2:23][CH2:24]2)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH:13][C:27]([C@@H:26]1[C@H:25]2[CH2:30][C@H:22]([CH2:23][CH2:24]2)[N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28]
Reactant: Nc1ccc2cc(Br)ccc2c1N
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)Nc1ccc2cc(Br)ccc2c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 6-bromonaphthalene-1,2-diamine (1.08 g, 4.56 mmol), and (1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.10 g, 4.56 mmol) and HATU (2.08 g, 5.47 mmol) in methylene chloride (45 mL) was added DIPEA (3.98 mL, 22.79 mmol). The mixture was stirred at room temperature for two hours. Upon completion, the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with water. The aqueous layer was back extracted with ethyl acetate twice. The combined organic layers were washed with brine, concentrated, and purified by normal phase chromatography (30-80% ethyl acetate (5% MeOH) in hexanes) to give (1S,3S,4R)-tert-butyl 3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.01 g, 95%). LCMS-ESI+: calc'd for C22H26BrN3O3: 459.12 (M+); Found: 460.9 (M+H+).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OCC)(=O)C>>[CH3:10][C:7]1[C:2]([C:1]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(C)=O
Product: Cc1ccccc1C(=O)O

Procedure:
2f (4.7 g, 9.3 mmol) and n-propanethiol (5.1 mL, 6 eq) were mixed in dimethylformamide (70 mL), potassium t-butoxide (5.7 g, 5 eq) was added thereto, and the mixture was stirred at 135° C. for 2.5 hours. After cooling, the reaction solution was transferred into a mixture of toluene (200 mL) and distilled water (200 mL), methanesulfonic acid (5 g) was added thereto, and the mixture was then stirred. Thereafter, saturated aqueous sodium bicarbonate was added until the aqueous phase became alkalized. Liquid separation was performed, extraction with toluene (200 mL×3) was performed, and the organic phase was washed with distilled water (200 mL×2). The resultant was dried over magnesium sulfate and concentrated. The resulting crude product was purified by recrystallization from THF. Thus, 3.47 g of a free base substance of the object product was obtained. This product was dissolved in ethyl acetate, a solution of benzoic acid (1 eq) in ethyl acetate was added, and the solvent was removed by distillation. The resultant was suspended in ether and collected by filtration, thereby obtaining the object product 2-benzoate. Also, 3f was used as a starting material instead of 2f to obtain 3. This product was converted to methanesulfonate, and the object product 3-methanesulfonate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:2].Br[CH2:14][CH2:15][CH2:16][Cl:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:14][CH2:15][CH2:16][Cl:17])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(OCCCCl)c1
Yield: 68.7 %

Procedure:
To a solution of ethyl-3-hydroxybenzoate (5.0 g, 30 mmol) in acetone (250 ml) at rt was added 1-bromo-3-chloro-propane (5.67 g, 36 mmol) and K2CO3 (12.4 g, 90 mmol). The resulting suspension was heated to reflux where it was maintained for 25 h. After this time, the mixture was concentrated under reduced pressure and the resulting solid was partitioned between H2O and EtOAc. The organic phase was separated and the aqueous phase was extracted with additional EtOAc. The combined organic fractions were washed with 1N HCl and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the crude product. Purification by chromatography on silica eluting with 5% EtOAc/hexane gave 3-(3-chloro-propoxy)-benzoic acid ethyl ester as a colourless oil (5.0 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[OH:20].C(=O)(O)[O-].[Na+].O>CS(C)=O.Cl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[OH:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: N[C@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(N[C@H]2CCCC[C@H]2O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (671 mg, 4.42 mmol, Small Molecules, Inc.) and sodium bicarbonate (991 mg, 11.8 mmol) in DMSO (14.7 mL), and water (2.1 mL) is heated at 130° C. for 48 h. After cooling to room temperature, the mixture is diluted with 1 N HCl and extracted twice with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane to furnish the title compound as an off-white solid (527 mg, 68%). LC-ES/MS m/z 265.2 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[O:28][CH3:29])[CH:21]=[CH:20]1)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C(OC(C)(C)C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[N:19]([CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:4][CH2:3][OH:2])[CH:20]=[CH:21]2
Reactant: COC(=O)C(C(=O)OC(C)(C)C)C(c1cccnc1)n1ccc2cccc(OC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2ccn(C(CCO)c3cccnc3)c12
Reaction time: 4 h

Procedure:
2-[(7-Methoxy-indol-1-yl)-pyridin-3-yl-methyl]-malonic acid tert-butyl ester methyl ester (0.200 g) was dissolved in toluene (50 ml) and treated with p-toluenesulfonic acid (0.102 g). The mixture was brought to reflux temperature and stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and aqueous bicarbonate solution, the organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to afford 3-(7-methoxy-indol-1-yl)-3-pyridin-3-yl-propan-1-ol as an oil which was purified by column chromatography (ethyl acetate-hexane 3:7).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[OH-].[Li+].[CH3:15][O:16][CH2:17][CH2:18][OH:19]>>[CH3:15][O:16][CH2:17][CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COCCO
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Product: COCCOc1ccc(C(=O)O)cn1
Temperature: 40 °C
Yield: 67 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 67% yield starting from ethyl 6-chloronicotinate and 2-methoxyethanol. The reduction was performed using 3 equiv of lithium hydroxide while heating to 40° C. over weekend. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, 1 H), 8.13 (dd, 1 H), 6.91 (d, 1 H), 4.42-4.47 (m, 2 H), 3.62-3.68 (m, 2 H), 3.29 (s, 3 H); MS (ESI) m/z 198[M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[C:14]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[N:13][N:12]=[N:11]1>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([C:14]3[NH:13][N:12]=[N:11][N:10]=3)[CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: O
Product: Fc1cnc(Cl)nc1Nc1cccc(-c2nnn[nH]2)c1

Procedure:
A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimindine (1.2 equivalents) and 3-(tetrazol-5-yl)aniline (1 equivalents) in methanol:water (1:1; v/v) was heated at 60° C. for 24 h. Upon dilution with water and acidification, the solid formed was fitered, washed with water, dried and analyzed to give 2-chloro-5-fluoro-N4-[3–1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine (R926853). Alternatively this reaction can be achieved by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-yl)aniline (3 equivalents) in water (1:1; v/v) at 60° C. for 2–3 hours or at room temperature for 24 h to give 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz), 7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H, J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:33][C@@H:34]([CH:44]([CH3:46])[CH3:45])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Mg].BrCCBr>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([OH:14])[CH2:33][C@H:34]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]([CH3:45])[CH3:46])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](C=O)N2C(=O)OC(C)(C)C)ccc1OC
Reactant: CC(C)[C@H](CCl)COCc1ccccc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](O)C[C@H](COCc3ccccc3)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Alternatively, A solution of 27 g of aldehyde 7 in 30 mL of tetrahydrofuran is added to a room-temperature solution of the Grignard reagent prepared by refluxing 20 g of ((S)-2-chloromethyl-3-methyl-butoxymethyl)-benzene with 3.2 g of magnesium in 120 mL of tetrahydrofuran containing 1.3 g of 1,2-dibromoethane for 4 h. The reaction is stirred for 1 h at room temperature, then 100 mL of 2 N sulfuric add is added. The mixture is stirred until the excess magnesium has dissolved, then the phases are separated and the organic phase washed with 50 mL of 12% sodium chloride solution. The organic phase is concentrated in vacuum to give e.g. 42.6 g of the crude alcohol 8 as an oil.
Reaction SMILES: [CH2:1]([CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH2:1]([CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:9]([O:11][CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)C(Cc1ccccc1)c1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)C(Cc1ccccc1)c1c[nH]c2ccccc12

Procedure:
To a solution of α-benzylindole-3-acetic acid (12 g) in methanol (200 mL), was added 2 mL of concentrated H2SO4 ; the mixture was stirred at reflux temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to a volume of about 50 mL, then diluted with 200 mL of toluene. The toluene solution was washed with water, saturated NaHCO3 solution, and again with water. On evaporation, if afforded 12.3 g (97.6% crude yield) of product as a light brown viscous oil. The crude product slowly crytallized on standing at room temperature. It was triturated with heptane to give fine white crystals, m.p. 62°-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([CH3:15])[CH2:11][C:12](O)=[O:13].C(Cl)(=O)C([Cl:19])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([CH3:15])[CH2:11][C:12]([Cl:19])=[O:13]
Reactant: COc1ccccc1CC(C)CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1CC(C)CC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-methoxyphenyl)-3-methylbutyric acid (24 mmol, crude from previous reaction) in dichloromethane (36 mL) was added oxalyl chloride (2 M in DCM, 36 mL). The reaction was stirred for 1 h at room temperature. All volatiles were removed in vacuo and the crude residue used without further purification.