Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>O1CCCC1>[CH:10](=[N:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CSc1ccc(N)nc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(N=Cc2ccccc2)nc1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
5-(methylthio)-2-aminopyridine (185 g) was dissolved in 2 L tetrahydrofuran, and then 500 mL titanate tetraisopropyl and benzaldehyde (155 g) were added. The reaction mixture was heated for reflux overnight, then cooled to room temperature, and 10 L water was added. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. After filtration, the residual solution was removed under reduced pressure to obtain the target compound (200 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[CH3:36][S:37]([NH:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1)(=[O:39])=[O:38]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:51][CH2:50][CH:47]2[CH2:48][O:49][C:44]3[CH:43]=[CH:42][C:41]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:52][C:45]=3[O:46]2)=[CH:2]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
3-Indolebutyric acid (1.7 g, 8.2 mmole), 1-hydroxybenzotriazole hydrate (1.3 g, 9.8 mmole) and 1,3-diisopropylcarbodiimide (1.5 ml, 9.8 mmole) were combined in 200 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine (2.0 g, 8.2 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Product fractions were concentrated and washed with a minimum amount of THF to remove a by-product and give 3.0 g (82%) of the desired product, (7-methylsulfonylamino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as an oily white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: ClCCCN1CCOCC1
Product: O=C(c1cn(CCCN2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 52 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 4-(3-chloro-propyl)-morpholine gave the title compound in 52% yield. ES-MS m/e (%): 494.6(M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](Cl)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1.C([O-])(O)=O.[Na+]>COCCOC.[Zn]>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][C:3](=[O:14])[N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:12])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=1
Reactant: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: COCCOC
Product: Cn1c(=O)oc2ccc(C(=O)Cc3ccc(Br)cc3C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (935 mg, obtained in Example 116, step 5) in CH2Cl2 (15 mL) were added two drops of DMF and oxalylchloride (0.66 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again. The resulting solid was dried at high vacuum over night to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (633 mg) in 1,2-dimethoxyethane (10 mL) was added tetrakis(triphenyl-phosphine)palladium(0) (56 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (10 mL) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-trifluoromethyl-benzene (1.54 g, [CAS Reg. No. 335013-18-8]) in 1,2-dimethoxyethane (10 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 18 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=1:1) to give the title compound as a yellow oil (944 mg, 47%). MS (neg. ion, m/e)=414.1 [(M−H)−].
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH:6]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])[C:7]([NH2:9])=[NH:8].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:34][S:35]([O:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:49](=[NH:51])[NH2:50])[CH:45]=2)[CH:40]=1)(=[O:37])=[O:36]>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36].[NH:6]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:49](=[NH:50])[NH2:51])[CH:45]=2)[CH:40]=1)=[O:14])[C:7]([NH2:9])=[NH:8]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: N=C(N)Nc1cccc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)Nc1cccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)c1
Yield: 34.7 %

Procedure:
To a solution of 4.7 g of m-guanidinobenzoic acid methanesulfonate in 50 ml of anhydrous pyridine, was added 4.4 g of DCC. To the mixture, while being cooled in ice and stirred, was added 5.0 g of 6-amidino-2-naphthol methanesulfonate. After having been stirred for 24 hours, the reaction mixture was freed from the insolubles by filtration and the filtrate was mixed with ether. The oily substance which was formed was crystallized by adding ethyl acetate. Recrystallization from a mixture of methanol and ether gave 3.2 g of 6-amidino-2-naphthyl 3-guanidinobenzoate dimethanesulfonate.
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:25]12(CC1)C1C(=CC(C=O)=CC=1)C[CH2:26]2.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][NH:9][CH2:8][C:7]2[CH:6]=[C:5]3[C:4](=[CH:24][CH:23]=2)[C:1]2([CH2:2][CH2:3]2)[CH2:26][CH2:25]3)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc2c(c1)CCC21CC1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)c1cccc(CCNCc2ccc3c(c2)CCC32CC2)c1
Yield: 88 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 2′,3′-dihydro-spiro-[cyclopropane-1,1′-[1H]indene]-5′-carboxaldehyde (prepared as described in example S108) (68 mg, 0.40 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (75 mg, 0.40 mmol) and sodium borohydride (22 mg, 0.59 mmol). The desired product (120 mg, 88%) was isolated without further purification as a colorless oil. MS (ISP) 346.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1cccc(N)c1OC
Product: COc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1OC

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 2,3-dimethoxyaniline (69 μl, 0.486 mmol) similar to Example 11 and isolated as a white solid (169 mg). 1H NMR (CDCl3): 8.85–8.82 (m, 1H), 8.48 (d, J=7.8 Hz, 1H), 7.87–7.82 (m, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.40–7.35 (m, 2H), 7.10 (t, J=8.4 Hz, 1H), 6.73 (d, J=1.5 Hz, 1H), 7.00 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:21]1[CH:26]=[N:25][C:24]([N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)=[CH:23][N:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Clc1cnc(-n2cncn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3cnc(-n4cncn4)cn3)CC2)nc1
Temperature: 90 °C

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (50 mg, 0.18 mmol) from step 3, Example 5 and 2-chloro-5-(1H-1,2,4-triazol-1-yl)pyrazine (35.6 mg, 0.20 mmol) were added in NMP (0.89 mL), then potassium carbonate (73.8 mg, 0.53 mmol) was added and the reaction was heated to 90° C. overnight. The reaction was cooled to room temperature, water (10 mL) was added and drops of acetic acid were added to adjust pH value to ˜4, extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The water phase was back extracted with ethyl acetate (10 mL×2). The organic phase were combined and dried by magnesium sulfate, filtered and concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 30% ethyl acetate/hexane to give the title compound as a white solid.
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([CH3:14])=[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:8]=[C:7]2SC.[I-].[CH3:24][C:25]1[S:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[N+:29]=1[CH3:30].C(N(CC)CC)C>CN(C)C=O>[I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[N:8][C:7]2=[CH:24][C:25]1[S:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[N+:29]=1[CH3:30]
Reactant: Cc1sc2ccccc2[n+]1C
Reactant: COc1ccc2c(c1)c(SC)nc(-c1ccccc1)[n+]2C
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=Cc1sc3ccccc3[n+]1C)N=C(c1ccccc1)N2C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (1.41 mmol) 6-Methoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 412 mg (1.41 mmol) 2,3-dimethyl-benzothiazol-3-ium iodide were dissolved in 2.0 ml dimethylformamide and 571 mg (0.79 ml, 5.64 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue was washed with water and methanol.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH2:8])=[S:7])(=[O:3])[CH3:2].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=[O:12].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:4][CH2:5][C:6]1[S:7][CH2:13][C:11]([CH2:10][Cl:9])([OH:12])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(N)=S
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)OCC1=NC(O)(CCl)CS1
Temperature: 25 °C
Reaction time: 87 h
Yield: 92 %

Procedure:
A mixture of 5.33 g of 2-acetoxythioacetamide prepared according to Example 2, 5.21 g of 1,3-dichloroacetone, 6.88 g of sodium bicarbonate and 20 ml of 1,2-dichloroethane was stirred at room temperature for 87 hours. The mixture was filtered to remove insoluble inorganics and concentrated under reduced pressure to an oil. The oil was taken up in 4 mls of 1,2-dichloroethane and 25 mils of cyclohexane added dropwise. The slurry was stirred for 1 hour at 0° C. and then filtered. The precipitate was washed with cyclohexane and dried at room temperature under reduced pressure. The product 2-acetoxymethyl-4-chloromethyl-4-hydroxy-thiazoline was obtained in 92% yield (8.25 g).
Reaction SMILES: C[C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH:4]=[CH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:9]=1[CH3:25])=[O:7].[F:30]C1C=CC=CC=1C=O.C(O)C.[OH-].[K+]>C(OCC)(=O)C>[F:30][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH:4]=[CH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:9]=1[CH3:25])=[O:7]
Reactant: Cc1ccccc1C=CC(=O)c1c(C)n(CCN2CCOCC2)c2ccccc12
Reactant: O=Cc1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)C=Cc2ccccc2F)c2ccccc2n1CCN1CCOCC1
Yield: 54 %

Procedure:
Following a procedure similar to that described in Example 20A above, 14.75 g. (0.0516 mole) of 3-acetyl-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole (Example 20A) was reacted with 2-fluorobenzaldehyde in 260 ml. of ethanol in the presence of 3.44 g. (0.061 mole) of potassium hydroxide pellets and the product, in the form of the free base, recrystallized from ethyl acetate to give 10.0 g (54%) of 3-(2-fluorocinnamoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p. 113°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][N:3]=1.S([O-])([O-])=[O:11].[Na+].[Na+].[OH2:16]>C(O)(C)(C)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]([OH:11])[CH2:9][OH:16])=[CH:6][CH:7]=1
Reactant: O
Reactant: C=Cc1ccc(Cl)nc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: OC[C@H](O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a cooled 5° C., stirred slurry of AD_Mix-β® (150 g) in water (530 mL) and t-butanol (450 mL) was added a solution of 2-chloro-5-vinylpyridine (15.0 grams) in t-butanol (80 mL). After 6 hours, solid sodium sulfite (160 grams) was added and the resulting slurry was allowed to stir at ambient temperature for 30 minutes. This mixture was extracted with ethyl acetate (3 times), the combined organic layers were washed with saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo. The resulting oil was chromatographed on 500 grams of silica gel eluting with a gradient of ethyl acetate (70-80%) /hexanes to afford the title compound as a colorless oil, 17.8 grams 1H NMR (400 MHz, CDCl3): δ=8.35 (s,1H); 7.71(d,1H); 7.30(d, 1H); 4.85 (dd, 1H); 3.63 (dd,1H).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[C:5]([OH:20])[CH:4]=1)#N.[OH-:21].[Na+].Cl.C[OH:25]>O1CCOCC1>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[C:5]([OH:20])[CH:4]=1)([OH:25])=[O:21]
Reactant: CO
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Yield: 30 %

Procedure:
A mixture of 5-(4-cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D14) (4.00 g, 15.0 mmol) and 6 M NaOH (30 mL) in methanol (60 mL) and 1,4-dioxane (60 mL) was refluxed for 5 days. The mixture was cooled on an ice bath and acidified with 6 M HCl, then extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate to give 5-(4-carboxy-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1.29 g, 30%). Silica gel column (3:7 to 2:8 hexane/ethyl acetate) of the filtrate followed by trituration with ethyl acetate gave another 1.00 g (23%).
Reaction SMILES: [F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:38][C:39]1[NH:43][N:42]=[C:41]([NH2:44])[CH:40]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11]([NH:44][C:41]2[CH:40]=[C:39]([CH3:38])[NH:43][N:42]=2)[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Agent: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 105 °C
Reaction time: 72 h
Yield: 30.3 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxyquinazolin-4-ol (450 mg, 1.4 mmol) were added phosphoryl tribromide (3.14 g) and toluene (4 mL) followed by DIEA (0.488 mL, 2.8 mmol). The mixture was heated at 105° C. for 1 h. The mixture was allowed to cool and was partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (300 mg, 3.1 mmol) in DMF (4 mL) and the mixture was stirred at rt for 3 days. The crude mixture was purified by preparative HPLC (Varian C-18 reverse phase column, eluting with a gradient of solvent B=0.05% formic acid/ACN and solvent A=0.05% formic acid/H2O/5% ACN) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (170 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 3.95 (s, 3H) 5.91 (s, 1H) 7.38 (d, J=7.91 Hz, 1H) 7.56 (t, J=8.10 Hz, 1H) 7.93-8.06 (m, 2H) 8.19 (d, J=8.10 Hz, 1H) 8.66 (s, 1H) 10.53 (br s, 1H) 12.15 (br s, 1H); LC-MS (ESI) m/z 401 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19])=O.O.[NH2:21][NH2:22]>CN(C1C=CN=CC=1)C>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:22][N:21]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Yield: 49.7 %

Procedure:
Prepared as in Example 104 from [2-fluoro-3-chlorophenyl](4-methoxy-2-methylphenyl)methanone (1.26 g, 4.52 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.613 g) as a yellow solid.
Reaction SMILES: [Br-:1].O[CH:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH2:6][CH2:7]2)[CH2:4]1.[H-].[Na+].IC.O.[CH3:21][O:22]CCOC>>[Br-:1].[CH3:21][O:22][CH:6]1[CH2:7][CH:8]2[CH2:9][CH2:10][N+:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:3]2
Reactant: CCCCC[N+]12CCC(CC1)C(O)C2
Reactant: COCCOC
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCCC[N+]12CCC(CC1)CC2OC
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of (±)-3-hydroxy-1-pentylquinuclidinium bromide (20 g, 72 mmol) in dry 1,2-dimethoxyethane (150 ml) at 0° C., under nitrogen, was added sodium hydride (3.48 g, 60% in mineral oil, 86.8 mmol) and then iodomethane (11.3 ml, 181 mmol). The temperature was allowed to rise to room temperature overnight. Water (200 ml) was added and the mixture was extracted with 6×100 ml dichloromethane. Drying and evaporation gave an oily residue which, after trituration with petrol ether, gave the title compound as a crystalline solid. Yield 23.9 g (That the yield was more than 100% is explained by the fact that there is a mixture of bromide and iodide as counter ions.).
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[O:9]1[CH:13]=[CH:12][C:11]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10]1
Reactant: Oc1cccnc1Br
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Oc1cccnc1-c1ccoc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
2-Bromopyridin-3-ol (200 mg, 1.15 mmol), 3-furan boronic acid (574 mg, 1.38 mmol), sodium carbonate (365 mg, 12.8 mmol) and Pd2(dppf)2Cl2 (187 mg, 0.23 mmol) were dissolved in dimethoxyethane/water 2 mL/1 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(furan-3-yl)pyridin-3-ol (50 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1OCc1ccccc1

Procedure:
4-bromo-2-fluorophenol (2.557 g, 13.39 mmol) and (bromomethyl)benzene (1.590 ml, 13.39 mmol) in DMF (20 ml) were treated with K2CO3 (3.70 g, 26.8 mmol) overnight. The reaction was then diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated to provide the title compound. LCMS (APCI) m/e 282 (M+H).
Reaction SMILES: [Cl-:1].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C.C([Li])CCC.[CH:32]([C:34]1[C:39]([O:40]C(=O)C)=[C:38]([CH2:44][O:45]C(=O)C)[C:37]([CH2:49][O:50]C(=O)C)=[CH:36][N:35]=1)=O>CCCCCC>[ClH:1].[CH:32]([C:34]1[C:39]([OH:40])=[C:38]([CH2:44][OH:45])[C:37]([CH2:49][OH:50])=[CH:36][N:35]=1)=[CH2:2]
Reactant: [Cl-]
Reactant: CC(=O)OCc1cnc(C=O)c(OC(C)=O)c1COC(C)=O
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C=Cc1ncc(CO)c(CO)c1O
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 2 liter flask is charged with one equivalent of methyl triphenylphosphonium chloride and 600 ml. of anhydrous diethyl ether. This solution is cooled to 0° C. and one equivalent of n-butyllithium in hexane is introduced over a thirty minute period under nitrogen. When addition is complete, the solution is aged an additional 30 minutes at 0°-5° C. Then a solution of one equivalent of 2-formyl-3-acetoxy-4,5-diacetoxymethyl pyridine in 250 ml. of anhydrous ether is added dropwise with stirring over a one hour period. The reaction mixture is then aged 16 hours at room temperature, and is then cooled to 0° C. and filtered. The filtrate is concentrated to dryness under reduced pressure and treated with a mixture of 500 ml. of 2.5 N hydrochloric acid and 300 ml. of ethyl acetate. After shaking well, the organic phase is separated and discarded. The aqueous phase is extracted with 2 more 300 ml. portions of ethyl acetate and these too are discarded. The aqueous phase is then refluxed with stirring under nitrogen for 3 hours and after cooling is poured onto excess aqueous sodium bicarbonate. The crude, solid, free base is isolated by filtration and air dried. This crude solid is taken up into 300 ml. dry tetrahydrofuran and saturated with dry hydrogen chloride at 0° C. Then 300 ml. dry diethyl ether is introduced and the desired hydrochloride crystallized. It is isolated by filtration and dried in vacuo.