Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].Br[C:20]1[CH:21]=[C:22]([C:27]2[N:28]=[N:29][N:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=2)[C:23]([NH2:26])=[N:24][CH:25]=1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=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>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[C:2]([F:1])[CH:3]=2)=[CH:21][C:22]=1[C:27]1[N:28]=[N:29][N:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: O=C(c1ccc(B(O)O)cc1F)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2cc(-c3ccc(C(=O)N4CCOCC4)c(F)c3)cnc2N)nn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of (3-fluoro-4-(morpholine-4-carbonyl)phenyl)boronic acid (269 mg, 1.06 mmol) and of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (250 mg, 0.886 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (863 mg, 2.65 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (51 mg, 0.04 mmol) was added and allowed to stir at 120° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5% MeOH in DCM to afford 125 mg (yield: 34.43%) of the title compound as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[C:4]([F:12])[CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=C1CCc2c(F)cc(Br)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(Br)cc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of 6-bromo-4-fluoroindan-1-one (57 mg, 0.26 mmol) in trifluoroacetic acid (1.1 mL) was added triethylsilane (103 μL, 0.65 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0) to give a crude 6-bromo-4-fluoroindane (61 mg) as a yellow oil. The resultant was used in the next step without further purification. (2) The above crude product was treated in a similar manner to Reference example 41-(1) to give a crude methyl 7-fluoroindane-5-carboxylate. The resultant was used in the next step without further purification. (3) The above crude product was treated in a similar manner to Reference example 43-(2) to give a crude (7-fluoro-2,3-dihydro-1H-inden-5-yl)methanol. The resultant was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][N:10]([S:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])[C:9]=2[CH:26]=1)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([S:14]([N:10]2[C:9]3[CH:26]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12][CH2:11]2)(=[O:15])=[O:16])[CH:22]=1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (7.1 g, 17.8 mmol) in tetrahydrofuran (100 mL) and methanol (50 mL) was treated with 3N NaOH (25 mL, 75 mmol, 4.2 equiv.). The mixture was stirred at 45° C. for 1.5 hours. The organic solvents were then removed and the residue acidified with HCl 3N (25 mL). The white precipitate which formed was filtered, washing with water, and dried under high vacuum. 4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid was obtained as a white solid, 6.79 g (99%), MS (ISP): m/e=382.0 (M−H), which was used crude in the following reaction.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1NC1CCCC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Cyclopentylamine and potassium carbonate were added to a DMF solution of 4-chloro-2-fluorobenzonitrile, followed by stirring at 100° C. for 12 hours. By post-treating the reaction liquid, 4-chloro-2-(cyclopentylamino)benzonitrile was obtained.
Reaction SMILES: C[CH2:2][O:3]C(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([CH2:52][CH3:53])=[C:44](Br)[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([CH2:52][CH3:53])=[C:44]([CH:2]=[O:3])[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Product: CCc1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15, intermediate c) from (4R,9aR)-7-bromo-6-ethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[OH:23][CH2:24][CH2:25][CH2:26][NH:27][CH3:28]>>[OH:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:28])[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22]
Reactant: CNCCCO
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)CCCO)cc3)c2)o1

Procedure:
N-(3-Hydroxypropyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-(3-hydroxypropyl)-N-methylamine using method I.
Reaction SMILES: [OH:1][CH:2]([CH:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])[C:3]([O:5]C)=[O:4].[OH-].[Na+].Cl>CO>[OH:1][C@H:2]([C@H:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(O)C(C)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](C1CC1)[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 2-hydroxy-3-cyclopropylbutanoate (0.62 g, 3.9 mmol) in MeOH (10 mL) was added aqueous NaOH (1.0 mL of a 5.5 M solution, 5.5 mmol). The mixture was stirred at ambient temperature for 18 h. The mixture was brought to pH 2 by the addition of 6 N aqueous HCl and solvents were removed under reduced pressure. The residue was dried under high vacuum for several hours. The residue was suspended in dichloromethane (15 mL) and stirred for 1 h. The solid was removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified on a Chiralpak AD column using 90:10:0.1 hexanes:2-propanol:TFA as eluant. Fractions containing the first-eluting peak were pooled and the solvents were removed under reduced pressure to give 2(R)-hydroxy-3(S)-cyclopropylbutanoic acid as a white solid. HPLC RT=1.98 min (Method A); 1H NMR 400 MHz, CDCl3, 4.36 ppm (d, J=2.9 Hz, 1H), 1.18 ppm (m, 1H), 1.00 ppm (d, J=7 Hz, 3H), 0.86 ppm (m, 1H), 0.54 ppm (m, 2H), 0.23 ppm (m, 1H), 0.18 ppm (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[OH-].[K+].[CH3:12]I>CO.O.C(Cl)(Cl)Cl>[CH3:12][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: CI
Reactant: COc1ccc[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cccn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a stirring reaction mixture of 3-methoxypyridine-2-one (0.2 g, 1.6 mmol) and KOH (0.18 g, 3.2 mmol) in methanol was added MeI (0.68 g, 4.8 mmol) dropwise in condenser equipped round bottom flask. After overnight stirring at room temperature revealed quantitative formation of product. Reaction mixture was then diluted with water (35 mL) and CHCl3 (40 mL). Organic layer was washed with water (1×35 mL), brine (1×30 mL) and dried over Na2SO4 and solvent was evaporated in vacua to yield pure 141a (0.20 g, 89%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.66 (m, 1H), 6.35 (d, J=7.4 Hz, 1H), 5.83 (t, J=7.1 Hz, 1H), 3.52 (s, 3H), 3.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.01, 149.56, 128.81, 111.91, 104.31, 55.44, 37.10.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cccc2cccnc12
Reactant: Brc1ccc2ccccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc2cc(Nc3cccc4cccnc34)ccc2c1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 8-aminoquinoline (6.81 grams, 47.2 mmoles), 2-bromonapthalene (9.58 grams, 46.3 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.84 grams, 0.92 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.6 grams, 0.92 mmoles), sodium tert-butoxide (8.86 grams, 92.2 mmoles) and anhydrous toluene (90 mL). The contents of the flask were refluxed for sixteen hours; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (135 mL). The combined organic layers were concentrated in vacuo to yield a yellow solid. The solid was chromatographed on silica gel, eluting with a hexane/ethyl acetate gradient to afford 6.6 grams of the desired product as a yellow solid. 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.4 (bs, 1H), 8.05 (d, 1H), 7.6-7.9 (m, 5H), 7.25-7.5 (m,5H), 7.2 (d, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH:18]=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)#[N:21]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18][N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][C:20]#[N:21])[CH2:26][CH2:27]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCCN1CCNCC1
Reactant: O=CCCN1c2ccccc2CCc2ccccc21
Solvent: ClCCl
Product: N#CCCCN1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Reaction time: 16 h
Yield: 68.2 %

Procedure:
Na(Oac)3BH3 (171 mg, 0.80 mmol) were added to a solution of 3-(10,11-dihydro-dibenzo[b,f]azepine-5-yl)-propionaldehyde (100 mg, 0.40 mmol) and N-(3-cyanopropyl)-piperazine (122 mg, 0.80 mmol) in CH2Cl2 (10 ml). After 16 hours of stirring, the mixture was diluted with CH2Cl2 (50 ml) and washed with a saturated solution of NaHCO3. The organic phase was dried (Na2SO4) and evaporated. Purification using flash chromatography of the residue obtained yielded N-[3-(10,11-dihydro-dibenzo[b,f]azepine-5-yl)-propyl]-N′-(3-cyanopropyl)-piperazine (yield: 106 mg, 68%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-])=O)=[CH:9][C:8]=1[O:18][CH3:19])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[C:8]([O:18][CH3:19])=[CH:9][C:10]([NH2:15])=[CH:11][C:12]=1[O:13][CH3:14])[CH3:21]
Reactant: CCN(CC)CCOc1c(OC)cc([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCN(CC)CCOc1c(OC)cc(N)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a solution of the nitro compound (440 mg, 1.48 mmol) in ethanol (15 ml) was added ammonium formate (600 mg, 9.45 mmol) and 10% Pd on carbon (100 mg) and the reaction stirred at room temperature for 18 h. The mixture was filtered through Celite™, the filtrate concentrated in vacuo and partitioned between ethyl acetate and water. The ethyl acetate layers were dried (MgSO4) and concentrated in vacuo to give 4-(2-diethylaminoethoxyl)-3,5-dimethoxy aniline as an orange powder (360 mg) δH (CDCl3) 5.92 (2H, s), 4.02 (2H, t, J 5.9 Hz), 3.77 (6H, s), 2.99 (2H, t, J 5.9 Hz), 2.80 (6H, m) and 1.11 (4H, t, J 6.9 Hz). MS (ES+) 269 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]2=[O:26])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:27][N:28](C=O)C.C(OCC)(=O)C.N>[C-]#N.[Zn+2].[C-]#N.O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][CH:4]=2)[C:9]([O:11][CH3:12])=[O:10])[C:14](=[O:26])[CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C)C=O
Reactant: COC(=O)C(c1ccc(Br)cc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: N
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(c1ccc(C#N)cc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 2-(4-bromophenyl)-2-[4-(tert-butoxycarbonyl)-2-oxo-1-piperazinyl]acetate (1.28 g), zinc cyanide (211 mg), tetrakis (triphenylphosphine)palladium (139 mg) and DMF (10 ml) was stirred at 80° C. for 6 hours and cooled. To the reaction solution were added ethyl acetate, water and a little amount of ammonia solution. The organic layer was separated, washed with saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give yellow syrup of methyl 2-[4-(tert-butoxycarbonyl)-2-oxo-1-piperazinyl]-2-(4-cyanophenyl)acetate (1.01 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33](OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:32][C@H:31]1[C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[O:29])([CH3:26])([CH3:25])[CH3:24].[F-].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@@H:33]3[CH2:34][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C@H:31]([C:48](=[O:52])[N:49]([CH3:50])[CH3:51])[CH2:32]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dimethylformamide (8 ml) was added to 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (0.489 g; prepared as described in the starting materials for Example 22), (2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine (0.678 g) and cesium fluoride (0.697 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was evaporated under vacuum and the residue dissolved in methylene chloride/methanol and adsorbed onto silica. The product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the expected product were combined and evaporated. The residue was re-purified by column chromatography eluting with increasingly polar mixtures of ethyl acetate/methanol (100/0 to 92/8). The fractions containing the required product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as a colourless gum which crystallised on standing (0.36 g); 1H NMR Spectrum: (DMSO d6 @ 373K) 1.41 (s, 9H), 1.99 (m, 1H), 2.92-3.03 (m, 7H); 3.44 (m, 1H), 3.96 (s 3H), 4.14 (m, 1H), 4.70 (t, 1H), 5.10 (m, 1H), 7.22-7.30 (m, 2H), 7.44 (t, 1H), 7.62 (t, 1H), 7.84 (s, 1H), 8.40 (s, 1H), 9.30 (s, 1H); Mass Spectrum: (M+H)+ 560.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=3)[N:12]([CH2:25][CH2:26][CH2:27]O)[C:11]=2[C:10]([C:29]([O:31][CH3:32])=[O:30])=[CH:9][CH:8]=1.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(=O)([O-])O.[Na+].CN(C)C=O.O.C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:29]([O:31][CH3:32])=[O:30])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=3)[CH2:27][CH2:26][CH2:25][N:12]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ncc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.5 %

Procedure:
Methanesulfonyl chloride (1.8 mL, 23.1 mmol) was added to a stirred solution of methyl 4-chloro-2-[(3,5-dichloropyridin-2-yl)amino]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference example 123, 3.32 g, 7.73 mmol) and triethylamine (4.3 mL) in tetrahydrofuran (100 mL) at 0° C. The mixture was stirred at room temperature for 5 hr. The mixture was diluted, with aqueous sodium hydrogen carbonate, and the precipitate was collected by filtration. A mixture of the resulting mesylate and potassium carbonate (4.27 g, 30.9 mmol) in N,N-dimethylformamide (40 mL) was stirred at 80° C. for 2 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound as a colorless powder (2.37 g, 5.76 mmol, 75% in 2 steps).
Reaction SMILES: Cl.[Sn](Cl)Cl.[F:5][CH:6]([F:25])[N:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19](Cl)(=O)=O)=[CH:15][C:14]=2[F:23])[N:9]=[C:8]1[CH3:24].[Cl-].[Na+]>C(O)(=O)C>[F:25][CH:6]([F:5])[N:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][C:14]=2[F:23])[N:9]=[C:8]1[CH3:24]
Reactant: Cc1nn(-c2ccc(S(=O)(=O)Cl)cc2F)c(=O)n1C(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc(S)cc2F)c(=O)n1C(F)F
Temperature: 85 °C
Yield: 60.7 %

Procedure:
Gaseous hydrogen chloride was bubbled into a mixture of 3.29 g (0.0146 mole) of tin(II) chloride in 40 mL of acetic acid for about five minutes, causing it to become a clear solution. This solution was then heated to 85° C., and a hot solution of 1.66 g (0.00485 mole) of 4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenylsulfonyl chloride was added to the first solution. This reaction mixture was heated at 85° C. for 45 minutes. After cooling to room temperature, the resulting yellow solution was poured into 120 mL of hydrochloric acid. To this mixture was added 100 mL of a saturated aqueous solution of sodium chloride, and the resulting mixture was extracted with ethyl acetate, but the layers did not separate. The addition of a saturated aqueous solution of sodium chloride did effect a partial separation. The aqueous layer was extracted two more times with ethyl acetate, and all extracts were combined. After evaporation of the solvent under reduced pressure, the residue retained an odor of hydrochloric acid. Water was added to the residue, and this mixture was extracted three times with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and filtered. Following evaporation of the solvent under reduced pressure, the yellow residue that remained was dried under vacuum. This dried residue was placed on a column of silica gel and eluted with methylene chloride/ethyl acetate (2:1). After being dried under vacuum for several hours, 0.81 g of 4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorothiophenol was isolated as a yellow syrup. The NMR spectrum was consistent with the proposed structure. This reaction was repeated to obtain additional product for subsequent reactions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.[Na].[C:11]1([S:17]([OH:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][C:7]=1[S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: Oc1ccc(Br)cc1O
Reactant: O=S(O)c1ccccc1
Agent: [Na]
Product: O=S(=O)(c1ccccc1)c1cc(O)c(O)cc1Br

Procedure:
48.0 g of 4-bromo-1,2-benzenediol [cf. W. Rosermund, Ber. 62, 1262 and so forth (1923)] are oxidatively condensed with 33.4 g of the sodium salt of benzenesulphinic acid in a manner analogous to that described in Example 5a). Crystallisation from 1,2-dichloroethane yields 4-bromo-5-(phenylsulphonyl)-1,2-benzenediol in the form of colourless crystals having a melting point of 166°-168°.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C1CCCCC1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8]/[C:9](=[CH:22]\[N:23]([CH3:25])[CH3:24])/[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1CCCOc2ccc(Br)cc21
Reactant: COC(OC)N(C)C
Solvent: C1CCCCC1
Product: CN(C)/C=C1\CCOc2ccc(Br)cc2C1=O
Temperature: 25 °C
Yield: 67 %

Procedure:
7-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (10.0 g, 41.5 mmol) in dimethylformamide dimethylacetal (100 mL) was heated at 110° C. for 18 h. The reaction was allowed to cool to room temperature and cyclohexane (100 mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40° C. to yield 7-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one as yellow crystals (8.19 g, 67%). 1H NMR δ (ppm)(CDCl3): 7.83 (1 H, d, J=2.59 Hz), 7.74 (1 H, s), 7.46 (1 H, dd, J=8.51, 2.58 Hz), 6.88 (1 H, d, J=8.52 Hz), 4.27-4.19 (2 H, m), 3.14 (6 H, s), 2.76-2.69 (2 H, m).