Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[O:14]1[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15]1.B(F)(F)F.CCOCC.Cl>C1COCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:15][CH:16]([OH:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Fc1ccccc1F
Reactant: CCCCCCC1CO1
Agent: Cl
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(O)Cc1cccc(F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred solution of 1,2-difluorobenzene 1 (20.0 g, 0.175 mol) in dry THF (300 ml) was added dropwise a solution of 2.5 M n-butyllithium (68 ml, 0.17 mol) at −70° C. under dry nitrogen. The addition rate was such that the temperature did not rise above −60° C. After the addition was completed the reaction was stirred at −70° C. for 2 h. 1,2-Epoxyoctane (21.6 g, 0.169 mol) was added slowly followed by the dropwise addition of boron trifluoride etherate (21 ml, 0.17 mol). The mixture was allowed to warm to room temperature overnight, acidified with 10% hydrochloric acid and extracted into ether. The combined extracts were washed with sat. aqueous sodium chloride and evaporated to give a viscous liquid. Kugelrohr distillation (130° C., 0.15 mm Hg) yielded 1-(2,3-difluorophenyl)-octan-2-ol (30.8 g, 74%) which crystallised on standing; Vmax 3370 br (OH), 2950, 2920, 2850, 1620, 1590, 1480 s, 1280, 1205, 1070 br, 825, 775, and 730 cm−1, δH 0.88 (3 H, t, Me), 1.23-1.40 (10H, m, CH2), 1.40-1.58 (4 H, m overlapping br s, CH2CHOH and OH), 2.72 (1 H, ddd, J16, 8 and 2 Hz, ArCH2), 2.91 (1 H, ddd, J16, 6, and 2 Hz, ArCH2), 3.86 (1 H, m, CHOH), and 6.94-7.09 (3 H, m, ArH); m/z 242 (M+), 225, 198, 157, 139, 128, and 97.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([S:22]([C:25]3[CH:30]=[CH:29][N+:28]([O-])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:32])=[O:10])=[CH:4][CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([S:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)(=[O:23])=[O:24])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:32])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nn1nc(S(=O)(=O)c2cc[n+]([O-])cc2)c2ccccc2c1=O
Agent: [Pd]
Solvent: CO
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(S(=O)(=O)c2ccncc2)c2ccccc2c1=O
Yield: 18.8 %

Procedure:
The product from Example 196 (10 mg, 0.021 mmol) was treated with 10% Pd/C (5 mg) in MeOH (5 mL) under H2 (1 atm) for 12 hrs. The mixture was filtered, and washed with MeOH, concentrated, and the resulting residue was purified by HPLC (conditions from Example 10C) to afford 1.8 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.97-11.79 (br s, 1H), 8.96 (dd, J=4.5, 1.6, 2H), 8.52 (d, J=8.1, 1H), 8.39 (d, J=7.1, 1H), 8.12 (dd, J=12.0, 4.9, 1H), 8.03 (t, J=7.2, 1H), 7.96 (dd, J=4.5, 1.6, 2H), 7.41 (d, J=8.5, 2H), 7.29 (d, J=8.4, 2H), 3.68 (s, 2H); MS (ESI+) M/Z 455 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14]OC)[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1>[NH2:14][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CON=C(CCC(=O)O)c1ccc(Cl)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: NC(CCCO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
4-(4-Chlorophenyl)-4-(methoxyimino)butanoic acid (Intermediate 53) (6.43 g, 26.61 mmol) in tetrahydrofuran (30 mL) was cooled, under an atmosphere of nitrogen, in an ice-methanol bath. Borane-tetrahydrofuran complex (1.0M in THF) (93 mL, 93.12 mmol) was added dropwise over a period of 20 minutes. The resulting solution was allowed to warm to room temperature, stirred for 1 hour then heated at reflux for a further 6 hours. After cooling in ice-water the mixture was treated with water (20 mL) dropwise with stirring over 10 minutes. The mixture was again allowed to warm to room temperature and stirred for 2 hours before evaporating the bulk of the solvent. The residue was then cooled in ice-water and 50% NaOH (aq.) (20 mL) added dropwise with stirring. The resulting mixture was stirred and heated at 90° C. for 4 hours then cooled to room temperature and extracted three times with Et2O. The combined extracts were washed with water followed by brine, dried over MgSO4 and evaporated to dryness. The crude product was then purified by flash silica chromatography (eluent 0-10% 7N ammonia in MeOH/DCM) and pure fractions evaporated to afford 4-amino-4-(4-chlorophenyl)butan-1-ol (3.88 g, 73.0%) as a colourless, transparent gum.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.Cl>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: COCCO
Agent: Cl
Agent: [Na]
Solvent: O
Product: COCCOc1ccc2c(=O)[nH]cnc2c1
Yield: 58 %

Procedure:
Sodium (400 mg, 17 mmol) was added carefully to 2-methoxyethanol (10 ml) and the mixture heated at reflux for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (750 mg, 4.57 mmol) was added to the resulting solution and the mixture heated at reflux for 15 hours. The mixture was cooled and poured into water (250 ml). The mixture was acidified to pH4 with concentrated hydrochloric acid. The resulting solid product was collected by filtration, washed with water and then with ether, and dried under vacuum to give 7-(2-methoxyethoxy) 3,4-dihydroquinazolin-4-one (580 mg, 58%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7](N)=[CH:6][C:5]=1[O:13][CH3:14])([CH3:3])[CH3:2].N([O-])=O.[Na+].[I-:19].[K+]>Cl>[I:19][C:7]1[CH:6]=[C:5]([O:13][CH3:14])[C:4]([CH:1]([CH3:3])[CH3:2])=[C:9]([O:10][CH3:11])[CH:8]=1
Reactant: COc1cc(N)cc(OC)c1C(C)C
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Product: COc1cc(I)cc(OC)c1C(C)C
Reaction time: 0.33 h
Yield: 40.2 %

Procedure:
To a suspension of 4-Isopropyl-3,5-dimethoxy-phenylamine (1.28 g, 6.56 mmol) in 15% hydrochloric acid (20 mL) at 0° C. was added sodium nitrite (0.54 g, 7.87 mmol-dissolved in 4 mL water) dropwise. After stirring 20 minutes, potassium iodide (1.09 g, 6.56 mmol-dissolved in 4 mL water) was added slowly at 0° C. After stirring at room temperature for 18 hours, the reaction mixture was partitioned between ether and 10% aqueous sodium bisulfite solution. The ether layer was washed with water, dried using anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography eluting with hexane yielded 5-Iodo-2-isopropyl-1,3-dimethoxy-benzene (807 mg, 40%) as a white solid, MS (M+H)=307.
Reaction SMILES: [Cl-].[NH4+].O.[C:4]([O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=2[C:28]#[N:29])[CH2:15][CH2:14]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Fe].C(O)C>[C:4]([O:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=2[C:28]#[N:29])[CH2:17][CH2:18]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(OC(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1N1CCC(OC(=O)c2ccccc2)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Subsequently, ammonium chloride (3.4 g) and iron powder (18 g) were added to a mixed solvent of water (80 ml) and ethanol (240 ml), and the mixture was heated to 65° C. Thereafter, 1-(2-cyano-4-nitrophenyl)-4-piperidinyl benzoate (32.3 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (25.3 g), melting point: 154–155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1>>[C:25]([N:24]([CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(=O)N(CCN(C)C)c1ccc(N)cc1
Product: CC(=O)N(CCN(C)C)c1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The product was prepared according to general working method I from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and N-(4-amino-phenyl)-N-(2-dimethylamino-ethyl)-acetamide (142b).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[CH3:26][C:24]1[NH:23][N:22]=[C:21]([NH:20][C:12]2[N:11]=[C:10]([O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:25]=1
Reactant: Cc1ccccc1O
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccccc3C)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-methyl-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-o-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[CH2:9][OH:10])=[C:4]([F:14])[CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>CC(C)=O>[OH:12][CH2:11][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:3][C:4]=1[F:14])([CH3:13])[CH2:9][OH:10]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(CO)(CO)c1ccc(N)cc1F
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred solution of 2-(4-amino-2-fluorophenyl)-2-methylpropane-1,3-diol (1.5 g, 7.53 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (1.2 g, 15.18 mmol, 2.0 eq) and phenyl chloroformate (1.3 g, 8.28 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 1 h. The acetone was evaporated, and the resulting residue was diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and the solvent evaporated. The crude product was purified by silica CC using EtOAc/PE (3:2) as eluent to get phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)-3-fluorophenylcarbamate (1.7 g, 71%) as a white solid (TLC system: EtOAc/PE (7:3), Rf: 0.55).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.F[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1
Reactant: Fc1ccc2ccccc2c1
Reactant: CN1CCC(O)c2occc2C1
Product: CN1CCC(Oc2ccc3ccccc3c2)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].[Br:22][C:23]1[N:27]=[C:26](Cl)[S:25][N:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[Br:22][C:23]1[N:27]=[C:26]([C:10]2[CH:11]=[CH:12][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[C:6]([CH:9]=2)[C:7]#[N:8])[S:25][N:24]=1
Reactant: Clc1nc(Br)ns1
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C#N
Temperature: 120 °C
Yield: 48.2 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (D39) (280 mg), 3-bromo-5-chloro-1,2,4-thiadiazole (194 mg) and tripotassium phosphate (517 mg) in 1,2-dimethoxyethane (DME) (4 mL) and water (1 mL) under nitrogen was added Pd(Ph3P)4 (113 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added, the reaction mixture was filtered through the celite. The aqueous layer was extracted with EA for 3 times. the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated and purified by column chromatography to give 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D44) (152 mg) as a white solid. MS (ES): C12H10BrN3OS requires 323. found 324.0 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:2]=1.[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:12](\[NH2:13])/[C:11]1[CH:10]=[CH:9][C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:14]=1
Reactant: NO
Reactant: N#Cc1ccc(Oc2cccnc2)cc1
Solvent: CCO
Product: N/C(=N\O)c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-(Pyridin-3-yloxy)benzonitrile (486 mg, 2.48 mmol) was dissolved in ethanol (10.0 mL) then hydroxylamine (1.0 mL, 9.9 mmol) was added and the mixture was refluxed for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo to give the product which immediately formed yellow solid (565 mg, 100%) which was taken to the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ(ppm): 5.83 (2H, bs), 7.05 (2H, d, J=9.0 Hz), 7.43 (1H, ddd, J=8.4, 4.4, 0.8 Hz), 7.46 (1H, ddd, J=8.4, 2.7, 1.6 Hz), 7.72 (2H, d, J=8.8 Hz), 8.39 (1H, dd, J=4.5, 1.5 Hz), 8.41 (1H, d, J=2.8 Hz), 9.64 (1H, bs). 13C NMR (125 MHz, DMSO-d6) δ(ppm): 118.1 (CH), 124.8 (CH), 126.1 (CH), 127.4 (CH), 129.2, 134.5 (CH), 141.2 (CH), 144.9 (CH), 150.3, 153.0, 156.7. MS (FAB+): 230 (MH+). HRMS for C12H11N3O2 (MH+): calculated: 230.0930; found 230.0941.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:29]2=[N:30][C:31](=[O:38])[C:32]3[C:37]([N:28]2[NH:27][N:26]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3.[CH3:39][N:40]1[C:44]([CH2:45]Cl)=[N:43][CH:42]=[N:41]1>CN(C=O)C.O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[N:27][N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([O:38][CH2:45][C:44]3[N:40]([CH3:39])[N:41]=[CH:42][N:43]=3)=[N:30][C:29]=12
Reactant: Cn1ncnc1CCl
Reactant: O=c1nc2c(-c3ccccc3F)n[nH]n2c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nc2c(-c3ccccc3F)nnn2c2ccccc12
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
A solution of potassium hexamethyldisilazide in toluene (0.5 M, 4 ml, 2.0 mmol) was added at room temperature under nitrogen to a stirred solution of 3-(2-fluorophenyl)-1,2,3-triazolo[1,5-α]quinazolin-5-one (0.56 g, 2.0 mmol) in dry DMF (10 ml). The dark brown solution was stirred for 10 min followed by addition of a solution of 2-methyl-3-chloromethyl-1,2,4-triazole (0.35 g, 2.65 mmol) in dry DMF (3 ml). The red solution was stirred at room temperature for 3 days, then poured into water (120 ml) and the yellow precipitate collected. The material was dissolved in dichloromethane (50 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 5% methanol-dichloromethane, partly removed unreacted starting material. The crude product was hot-filtered and recrystallised from ethyl acetate to give 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[1,5-α]quinazoline (0.354 g, 47%) as a very pale yellow solid, m.p. 195-197° C. Found: C, 60.14; H, 3.61; N, 25.86. C19H14FN7O.0.25(H2O) requires C, 60.08; H, 3.85; N, 25.81%. δH (360 MHz; DMSO) 3.94 (3H, s), 5.82 (2H, s), 7.37-7.43 (2H, m), 7.46-7.58 (1H, m), 7.82 (1H, dd, J=7 and 7), 7.97 (1H, s), 8.01 (1H, ddd, J=7, 7 and 1), 8.16 (1H, ddd, J=8, 8 and 1), 8.29 (1H, d, J=8) and 8.61 (1H, d, J=8); m/z (ES+) 376 (M+H+).
Reaction SMILES: [H-].[Na+:2].[CH2:3]([O:6][NH:7][C:8](=[O:27])[C:9]1[C:14]([Cl:15])=[C:13]([NH2:16])[CH:12]=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:10]=1)[CH:4]=[CH2:5]>C1COCC1>[CH2:3]([O:6][N-:7][C:8](=[O:27])[C:9]1[C:14]([Cl:15])=[C:13]([NH2:16])[CH:12]=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:10]=1)[CH:4]=[CH2:5].[Na+:2]
Reactant: C=CCONC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[N-]C(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Temperature: 23 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
NaH (60% dispersion in mineral oil; 33 mg, 0.82 mmol, 1.05 equiv) was added to a stirred solution of N-(allyloxy)-4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)picolinamide (300 mg, 0.78 mmol, 1.0 equiv) in THF (7.8 mL) at 23° C. The vigorously bubbling off-white mixture was stirred at 23° C. for 1 h. The resulting homogeneous light tan solution was concentrated via rotary evaporation. The residue was slurried in hexane and vacuum filtered to afford an off-white powder (260 mg, 81%): mp 236-240° C. dec; 1H NMR (300 MHz, DMSO-d6) δ 7.59 (dd, J=9, 8 Hz, 1H), 7.34 (dd, J=9, 2 Hz, 1H), 7.00 (d, J=2 Hz, 1H), 6.18 (br s, 2H), 6.01 (m, 1H), 5.18 (m, 1H), 5.03 (m, 1H), 4.13 (m, 2H), 3.92 (d, J=1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)[CH2:24][CH2:25]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)C(c1ccccc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)C(c1ccccc1)c1ccc(OCCN2CCOCC2)cc1
Yield: 41.8 %

Procedure:
A stirring solution of compound 71 (1.5 g, 6.19 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.152 g, 6.19 mmol) and potassium carbonate (1.709 g, 12.38 mmol) in (1:1) DMF: acetone (60 mL) was heated to 60° C. for 16 h then concentrated. The crude residue was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated to afford compound 73 (0.92 g, 42%) after purification by ISCO-HPLC (20 to 100% ethyl acetate in hexanes).
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1)(=O)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O.C>C1(C)C=CC=CC=1.CO>[CH:2]([C:1]1[N:9]2[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=[CH:17][C:8]2=[CH:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(CNC(=O)C(C)C)nc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc2cnc(C(C)C)n2c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a suspension of methyl 6-[(isobutyrylamino)methyl]nicotinate (Preparation 26, 935 mg, 3.96 mmol) in toluene (10 mL) was added phosphoryl chloride (3.03 g, 1.84 mL, 19.8 mmol) and the mixture refluxed under nitrogen for 3 hours. The resulting dark solution was cooled at room temperature and concentrated in vacuo to give an oil. The oil was then dissolved in toluene (10 mL) and concentrated in vacuo again. The resulting residue was partitioned between EtOAc (20 mL) and saturated aqueous sodium hydrogen carbonate solution (2×5 mL). The organic layer was washed with brine (5 mL), dried over magnesium sulfate, filtered and evaporated to yield a dark oil, which was dissolved in methanol (10 mL), treated with charcoal and refluxed for 5 minutes. The mixture was filtered through Celite and the filtrate concentrated in vacuo to yield the title compound as a pale yellow oil (830 mg, 82%), which was used directly in the next stage without further purification.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=2)=[CH:7][CH:6]=1>>[F:3][C:4]([F:19])([F:20])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The titled compound was prepared by standard NaBH4 reduction of 4′-trifluoromethyl-biphenyl-3-carbaldehyde (quant.). 1NMR (400 MHz, CDCl3) δ ppm: 7.40, 7.70 (m, 8H), 4.79 (s, 2H).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.C1COCC1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([C:39](=[O:42])[CH2:40][Cl:41])=[CH:35][C:36]=2[Cl:38])[CH2:31][CH2:30]1>C1COCC1>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([C@H:39]([OH:42])[CH2:40][Cl:41])=[CH:35][C:36]=2[Cl:38])[CH2:31][CH2:30]1
Reactant: CN1CCc2cc(C(=O)CCl)cc(Cl)c21
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: CN1CCc2cc([C@H](O)CCl)cc(Cl)c21
Reaction time: 1 h

Procedure:
To a solution of (S)-Methyl-CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and BH3-THF (8 mL, 8 mmol) is added at the same time a solution of BH3-THF (19 mL, 19 mmol) and a solution of N-Methyl-5-chloroacetyl-7-chloro-indoline (37.98 mmol) in 19 mL of THF. Both solutions are added dropwise over 30 minutes. The solution is stirred for 1 hour and quenched with the slow addition of methanol (50 mL). The solution is concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[O:28]([NH2:30])[CH3:29]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([NH:30][O:28][CH3:29])=[O:14]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: CON
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CONC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
2-(2-Chloro-4-nitrophenyl)acetic acid (67.2 mmol) was dissolved in DMF (500 mL) to give a colorless solution. CDI (87 mmol) was added in one portion. The mixture was stirred at room temperature until bubbling of the solution ceased. Methoxylamine hydrochloride (87 mmol) was added poroom temperatureion wise, and the resulting mixture was stirred at room temperature over night. The resulting suspension was concentrated under reduced pressure to 100 mL and then diluted with EtOAc (1200 mL). The resulting solution was washed with water (2×700 mL) and the aqueous layer was extracted back with EtOAc (2×600 mL). The organic layers were combined and washed with sat. aq. NaHCO3 (1×1200 mL) and sat. aq. NaCl (1×1200 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(2-chloro-4-nitrophenyl)-N-methoxyacetamide as a solid (85%).