Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:21][N:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27]Cl)=[O:23])[CH2:19][C:17]=2[N:18]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C)C=O.ClCCl>[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:21][N:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[O:23])[CH2:19][C:17]=2[N:18]=1
Reactant: c1c[nH]cn1
Reactant: O=C(OCCCCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCCCn1ccnc1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Reaction time: 16 h
Yield: 30 %

Procedure:
Add sodium hydride (0.068 g; 2.25 equiv; 1.70 mmoles) to a solution of: 3-chloropropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (0.283 g; 1.0 equiv; 0.76 mmoles), and 1H-imidazole (0.105 g; 2.0 equiv; 1.54 mmoles) in dimethylformamide (2.4 mL). Stir the reaction mixture for 16 hours, then dilute with dichloromethane and wash with water. Extract the aqueous layer with dichloromethane twice. Concentrate the combined organic extracts and then purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford of 3-(1H-imidazol-1-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (0.0922 g; 30%) as a yellow solid: MS (m/z): 405(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:13][NH:12]2)=[O:10])=[CH:4][CH:3]=1.[O:25]([C:32]1[N:37]=[C:36]([C:38](Cl)=[O:39])[CH:35]=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:13][N:12]2[C:38]([C:36]2[CH:35]=[CH:34][N:33]=[C:32]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:37]=2)=[O:39])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(OC1CNN(C(=O)Cc2ccc(F)cc2)C1)N1CCOCC1
Reactant: O=C(Cl)c1ccnc(Oc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(Oc3ccccc3)n2)C1)N1CCOCC1
Reaction time: 12 h
Yield: 61 %

Procedure:
Morpholine-4-carboxylic acid 1-[2-(4-fluorophenyl)acetyl]-pyrazolidin-4-yl ester, 41, (354 mg, 1.05 mmol) and 2-phenoxypyrimidine-4-carbonyl chloride, 18, (345 mg, 1.47 mmol) are dissolved in dichloromethane (2 mL). 1.0 N NaOH (3 mL) is added dropwise at room temperature while vigorously stirring. The reaction is allowed to proceed for 12 hours after which time additional acid chloride, 18, is added and stirring continued for 3 hours. Additional acid chloride, 18, (83 mg) is added and stirring continued for an additional 12 hours. After which time the reaction is diluted with dichloromethane (50 mL) and washed with water (50 mL). The combined organic layers are washed with NaHCO3 (sat.) (50 mL) and brine (50 mL), dried, filtered and concentrated to provide a brown oil. The crude material is purified over silica (100% ethyl acetate to 5% methyl alcohol/ethyl acetate) afford 348 mg (61% yield) of the desired product as a viscous oil.
Reaction SMILES: C([O:8][C:9](=[O:20])[CH2:10][NH:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[O:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][CH2:10][C:9]([OH:20])=[O:8])=[O:13])[CH2:15][CH2:16]1
Reactant: O=C(CNC(=O)N1CCOCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CNC(=O)N1CCOCC1

Procedure:
Analogously to Example 7a), 4.8 g (18.3 mmol) of N-morpholinocarbonyl-glycine-benzyl ester in 100 ml of ethyl acetate are hydrogenated with 1 g of palladium (10%) on carbon to yield the title compound: 1H-NMR (300 MHz, CDCl3): 3.88 (s, 2H), 3.64 (s, 4H), 3.50 (s, 2H), 3.35 (s, 4H).
Reaction SMILES: [Br:1]C1C(C)=C(NCC2C=C(C(C)(C)C)SC=2C(O)=O)C=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([C:33]([CH3:36])([CH3:35])[CH3:34])[S:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:23][C:24]1[N:25]=[C:26]([C:33]([CH3:36])([CH3:35])[CH3:34])[S:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: Cc1c(Br)cccc1NCc1cc(C(C)(C)C)sc1C(=O)O
Reactant: COC(=O)c1sc(C(C)(C)C)nc1C
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(C(C)(C)C)nc1CBr

Procedure:
Using the same general procedure as described for the preparation of 102e, reaction of methyl 4-methyl-2-tert-butylthiazole-5-carboxylate with N-bromo-succinimide in carbon tetrachloride afforded 125a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(Br)c1ccccc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1C(C)c1ccccc1

Procedure:
The title compound, MS: m/e=322.1 (M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and (1-bromoethyl)benzene.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:11]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:6]([C:7]1[CH:8]=[N:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:11]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)n1cc(C#C[Si](C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnn(C(=O)OC(C)(C)C)c1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 62.5 %

Procedure:
tert-Butyl 4-((trimethylsilyl)ethynyl)-1H-pyrazole-1-carboxylate (3) (3.88 g 14.69 mmole) was dissolved in THF (40 mL) and cooled to 0-5° C. A 1M solution of tetra-n-butylammonium fluoride in THF (16 mL, 16 mmole) was added and the reaction was stirred for 20 minutes. The THF was evaporated and the residue was taken up in ethyl acetate (50 mL) and washed with water (×2) and with brine, then dried and evaporated. The residue was purified on a flash column (silica, eluting with 15% ethyl acetate in cyclohexane) to give the title compound (1.765 g, 62%). 1H-NMR (CDCl3, 500 MHz): δ 1.68 (s, 9H, 3.11 (s, 1H), 7.79 (s, 1H), 8.24 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:13](=O)[CH2:14]Br>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:13]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:14]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: Nc1ccccn1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Product: COc1ccc(-c2cn3ccccc3n2)cc1OC

Procedure:
The title compound, pale yellow solid, m.p. 96° C. and MS: m/e=254.1 (M+), was prepared in accordance with the general method of example 1 from 2-amino-pyridine and 3,4-dimethoxy-phenacylbromide.
Reaction SMILES: [F:1][C:2]1([F:15])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.Cl[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1>>[F:15][C:2]1([F:1])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([S:12][CH2:17][C:18]4[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=4)=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Reactant: COc1c(C)cnc(CCl)c1C
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c1C
Yield: 86 %

Procedure:
Analogous reaction of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol with 2-chloromethyl-4-methoxy-3,5-dimethylpyridine gives 2,2-difluoro-6-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, of m.p. 148°-149° C. (from acetonitrile), in 86% yield.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:10])[CH2:8][F:9])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[Br-].[K+].Cl[O-].[Na+]>S(=O)(O)[O-].[Na+].O.ClCCl>[C:1]([O:5][CH2:6][C:7](=[O:10])[CH2:8][F:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCC(O)CF
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OCC(=O)CF
Temperature: 0 °C
Yield: 93.5 %

Procedure:
A 2.5 L 4-necked sulfonation flask equipped with mechanical stirrer, dropping funnel, thermometer and an argon in/outlet, was charged with 141 g (938.8 mmol) 1-tert-butoxy-3-fluoro-propan-2-ol, 400 mL dichloromethane, 30.02 g (357.3 mmol) sodium bicarbonate, 400 mL de-ionized water and 10.68 g (89.78 mmol) potassium bromide. The two-phase system was cooled to 0° C. and 712.1 mg (4.56 mmol) 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) were added. To the resulting light orange mixture were added within 2 h 609.1 g (1.072 mol) sodium hypochlorite solution 13.1% while vigorously stirring whereupon the internal temperature transiently rose to 15° C. The reaction mixture was quenched at 0° C. with 9.71 mL (46.8 mmol) sodium bisulfite solution 38-40% leading to disappearance of the orange color. The phases were separated and the aqueous layer was extracted twice with 350 mL dichloromethane. The combined organic phases were washed with 400 mL brine, dried over sodium sulfate, filtered and evaporated to afford 130.02 g (93.5%) crude 1-tert-butoxy-3-fluoro-propan-2-one of 98.9% GC purity. 1H-NMR (CDCl3, 300 MHz): 5.13 (d, JH,F=48, —CH2—F); 4.15 (d, J=1.5, —CH2—O); 1.22 (s, C(CH3)3).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:9]([CH2:23]O)=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:12]=1.[OH-].[Na+].[BrH:32]>C(O)(=O)C.O>[Br:32][CH2:23][C:9]1[C:8]([O:7][C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([O:3][C:2]([F:29])([F:28])[F:1])[CH:5]=2)=[N:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: OCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)Oc1cccc(Oc2nn(-c3ccc(C(F)(F)F)cc3)nc2CBr)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-[3-(Trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole-4-methanol (i.e. the product of Example 5, Step I, 0.17 g, 0.4 mmol) was suspended in 33% hydrobromic acid in acetic acid (2 mL) and 48% hydrobromic acid in water (2 mL). The mixture was heated to reflux with stirring for 4 h. The reaction mixture was cooled to 0° C. and basified with 50% aqueous sodium hydroxide solution. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3×15 mL), and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to obtain the title compound (0.19 g) as a pale yellow solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][O:29][CH2:28][CH2:27][O:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][O:29][CH2:28][CH2:27][O:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2COCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2COCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
133 mg (0.28 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 6A. Yield: 132 mg (purity 60%, 68% of theory)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C1CCCCO1)[N:10]=[C:9]2[CH2:21][N:22]([CH3:34])[CH2:23][CH2:24][N:25](C)[C:26](=O)OC(C)(C)C.O.CC#N.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[CH2:21][N:22]([CH3:34])[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: COCCOc1ccc2c(c1)c(CN(C)CCN(C)C(=O)OC(C)(C)C)nn2C1CCCCO1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CNCCN(C)Cc1n[nH]c2ccc(OCCOC)cc12
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A solution of (R/S) tert-butyl N-[2-([[5-(2-methoxyethoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]methyl](methyl)amino)ethyl]-N-methylcarbamate (156 mg, 0.33 mmol, 1.00 equiv) in trifluoroacetic acid (3 mL) and dichloromethane (2 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP 18, 5 m, 19×150 mm; mobile phase, water with 50 mmol CF3COOH and CH3CN (10.0% CH3CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm to give 122.3 mg (70%) of N1-((5-(2-methoxyethoxy)-1H-indazol-3-yl)methyl)-N1,N2-dimethylethane-1,2-diamine trifluoroacetate as a colorless oil. 1H-NMR (300 MHz, D2O): δ 7.54 (d, J=9.0 Hz, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.16 (dd, J=9.0 Hz, 2.1 Hz, 1H), 4.78-4.72 (m, 2H), 4.20-4.13 (m, 2H), 3.80-3.74 (m, 2H), 3.60-3.42 (m, 4H), 3.36 (s, 3H), 2.89 (s, 3H), 2.70 (s, 3H) ppm. LCMS (method M, ESI): RT=1.00 min, m/z=293.0 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:20]=[C:21]([C:25]([NH:27][CH2:28][C:29]([NH:31][CH:32]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)[CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[O:26])[CH:22]=[CH:23][CH:24]=2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[C:8]1([CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:20]=[C:21]([C:25]([NH:27][CH2:28][C:29]([NH:31][CH:32]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)[CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[O:26])[CH:22]=[CH:23][CH:24]=2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1cccnc1
Temperature: 25 °C
Yield: 447.5 %

Procedure:
The compound of Example 105 (400 mg, 0.094 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) to result in a white solid (200 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension containing 27.0 g of 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid, 19.5 ml of oxalyl chloride, 270 ml of methylene chloride, and a few drops of N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. Separately, a few drops of carbon tetrachloride was added to a suspension of 3.08 g of magnesium in 6.4 ml of absolute ethanol, and then a solution of 19.2 ml of diethyl malonate in 12 ml of absolute ethanol was added dropwise to the suspension under heating at 50° C., and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then, toluene was added to dissolve the residue and the solution was again concentrated. To a solution of the residue in 30 ml of toluene, a solution of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride in 30 ml of toluene was added dropwise with stirring under ice cooling, and then stirring was continued for 2 hours at room temperature. The reaction mixture was added with 100 ml of 5% sulfuric acid, and was then extracted with diethyl ether. The extract was washed with brine, and then dried and concentrated to give 47.3 of brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18]C)=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.N[C:21]1N=C(C2C=C(Br)C=CC=2O)C=C(Cl)N=1>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH:17]([CH3:18])[CH3:21])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 68 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and 2-propanol provided 4-(5-bromo-2-isopropoxy-phenyl)-6-chloro-pyrimidin-2-ylamine (68% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH:21]1([C:24]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:25])[CH2:23][CH2:22]1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: O=C(O)C1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 0.063 ml cyclopropylcarboxylic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight at ambient temperature. The reaction mixture is evaporated. The residue is then purified by silica gel chromatography. 91 mg of the title compound are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=[CH2:15].[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]=[CH:14][CH:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=1)[CH2:16][CH:17]=[CH2:18]
Reactant: C=CCC(C=C)OCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCC(C=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Yield: 75.9 %

Procedure:
10 g of the compound (1), 4.8 g of methyl p-hydroxybenzoate and 4.4 g of potassium carbonate were refluxed in 2-butanone for 12 hours. The insoluble matter generated was filtered off, and the solvent was evaporated. The residue was purified by column chromatography, to obtain 9.3 g of the objective compound (2). (Yield: 76%)
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:29])=[C:6]([CH:24]=[C:25]([CH2:27][CH3:28])[CH:26]=1)[NH:7][C:8]([C:10]1[N:14](CC2C=CC(OC)=CC=2)[N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.COC1C=CC=CC=1>>[C:1]([C:4]1[C:5]([OH:29])=[C:6]([CH:24]=[C:25]([CH2:27][CH3:28])[CH:26]=1)[NH:7][C:8]([C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CCc1cc(NC(=O)c2nnnn2Cc2ccc(OC)cc2)c(O)c(C(C)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCc1cc(NC(=O)c2nnn[nH]2)c(O)c(C(C)=O)c1
Yield: 10.5 %

Procedure:
A mixture of 3'-acetyl-5'-ethyl-2'-hydroxy-1-(4-methoxybenzyl)-1H-tetrazole-5-carboxanilide (0.41 g), trifluoroacetic acid (15 ml) and methoxybenzene (1.0 g) was heated at reflux for 45 minutes. The mixture was then cooled, and the solvents were removed under reduced pressure. The residue was treated with aqueous ammonia (2 N; 10 ml), washed with diethyl ether (10 ml), and the aqueous layer was separated off, cooled in an ice-bath and acidified by treatment with concentrated hydrochloric acid. The resulting solid was filtered off to give 3'-acetyl-5'-ethyl-2'-hydroxytetrazole-5-carboxanilide (30 mg), m.p. 238°-240° C. (with decomposition).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[N+:14]([C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23]Cl)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[N+:14]([C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Yield: 71.6 %

Procedure:
To a solution of N-methyl-4-nitrophenethylamine (1.5 g) (J.O.C., [1956], 21, 45) and 2-[4-nitrophenoxy]ethyl chloride (1.55 g) (C.A., [1955], 49, 3163e) in acetonitrile (50 ml) was added potassium carbonate (1.25 g) and sodium iodide (1.2 g) and the suspension was stirred at reflux for 72 hours. After evaporation to dryness, the residual oily solid was partitioned between a 2N aqueous sodium bicarbonate solution and ethyl acetate. After two further extractions with ethyl acetate, the organic portions were combined, washed with a saturated aqueous brine solution, dried over magnesium sulphate, filtered and evaporated. The resultant orange solid (2.7 g) was crystallised from ethanol to give the title compound, (1.9 g), m.p. 74°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([N:9]1[C:10]2[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (7.7 g, 191.7 mmol) was added portionwise to a 0° C. solution of 4-methoxyindole (21.7 g, 147 mmol) in 750 mL of anhydrous DMF. After 15 min, the slurry was treated with benzyl bromide (17.5 mL, 147 mmol). The reaction mixture was allowed to warm to ambient temperature and stir overnight. The reaction mixture was poured into 1 L of H2O. The layers were separated, and the aqueous phase was extracted with EtOAc (2×200 mL). The combined organic layers were washed with H2O (4×500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2; hexanes) to give 32.9 g (138.6 mmol; 94%) of the title compound as a white solid. Electrospray MS 238 (M+1);