Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](O)=[O:6].S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([Cl:22])=[O:6]
Reactant: O=C(O)C(CCBr)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(CCBr)(c1ccccc1)c1ccccc1

Procedure:
4-Bromo-2,2-diphenylbutyric acid (compound (F), 23 g, 72 mmol) was suspended in 150 mL of chloroform, and 20 mL of thionyl chloride (270 mmol) was added dropwise. After addition of the thionyl chloride, 0.2 mL of dimethylformamide was added, and the resulting solution heated at reflux for about 4 hours. The reaction mixture was then concentrated under reduced pressure to provide 4-bromo-2,2-diphenylbutyric acid chloride (compound (G) as a pale yellow oil that was used int the following step without further purifiction.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br.[NH2:14][CH2:15][CH2:16][Br:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:14][CH2:15][CH2:16][Br:17])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCCBr
Agent: Br
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NCCBr)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
In 30 ml of chloroform were added 3 g of 4-nitrobenzoyl chloride, 3.3 g of 2-aminoethyl bromide hydrobromide and 3.9 ml of pyridine under ice cooling, and they were stirred at the same temperature for 1 hour. The reaction mixture was then washed with water, and the resulting organic layer was concentrated to obtain a crude product of 2-(4-nitrobenzoylamino)ethyl bromide. Afterward, the latter was recrystallized from hexane/ethanol, the resulting crystals were collected by filtration, washed and dried to prepare 2.9 g of 2-(4-nitrobenzoylamino)ethyl bromide (compound 46).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Br[C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[N:21][CH:22]=1>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.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([CH:18]=2)[CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OCc1cncc(Br)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1cncc(-c2ccc(F)cc2)c1
Reaction time: 2 h

Procedure:
13.2 g of 4-fluorobenzeneboronic acid and 10.8 g of sodium hydrogen-carbonate are initially introduced, and a mixture of 16.1 g of 5-bromo-3-hydroxymethylpyridine, 30 ml of water and 60 ml of toluene is added with stirring and under a protective gas. A further 14 ml of water, 28 ml of toluene and 0.5 g of tetrakis(triphenylphosphine)palladium (0) are subsequently added. The reaction mixture is heated to reflux and held at this temperature for 2 hours. After cooling, the mixture is subjected to conventional work-up, giving 5-(4-fluorophenyl)nicotinyl alcohol. The alcohol is subsequently oxidized by conventional methods to give 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: [CH3:1][C@@H:2]1[C:14]2=[CH:15][C:16]([CH:18]=[CH:19][C@:13]2([CH3:20])[C@@H:12]2[C@H:4]([C@H:5]3[C@:9]([CH3:22])([CH2:10][C@@H:11]2O)[C@@:8]([OH:30])([C:23]([CH2:25][O:26][C:27]([CH3:29])=[O:28])=[O:24])[CH2:7][CH2:6]3)[CH2:3]1)=[O:17]>CN(C)C=O.O1CCCC1>[C:27]([O:26][CH2:25][C:23]([C:8]1([OH:30])[C@:9]2([CH3:22])[CH:5]([CH:4]3[C:12](=[CH:11][CH2:10]2)[C@:13]2([CH3:20])[C:14](=[CH:15][C:16](=[O:17])[CH:18]=[CH:19]2)[C@@H:2]([CH3:1])[CH2:3]3)[CH2:6][CH2:7]1)=[O:24])(=[O:28])[CH3:29]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)C1(O)CCC2C3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C

Procedure:
(see Tetrahedron Letters, 2001, 42 (14): 2639-2642). Alternatively, methyl prednisolone 21-acetate is dissolved in a mixture of dimethylformamide and tetrahydrofuran and cooled in an ice bath. SO2 is bubbled into methanesulfonyl chloride and the mixture is added dropwise to the solution containing the solution of methyl prednisolone 21-acetate. The title product can then be isolated by standard aqueous workup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:20](O)=[O:21])=[CH:18][CH:19]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:20](=[O:21])[NH:10][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:9])=[CH:18][CH:19]=1)=[O:14]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: CC(N)c1cccc(Br)c1
Product: COC(=O)c1ccc(C(=O)NC(C)c2cccc(Br)c2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 1 from 1-(3-bromo-phenyl)-ethylamine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][CH2:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([O:17]CC)=O)[CH:13]=2)=[N:6][CH:7]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>Cl>[CH:31]1([NH:34][C:15](=[O:17])[CH2:14][N:12]2[CH:13]=[C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:20][CH2:21][C:22]4[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=4[F:30])[C:2]([F:1])=[CH:7][N:6]=3)[CH:10]=[N:11]2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: CCOC(=O)Cn1cc(Nc2ncc(F)c(NCc3c(F)cc(F)cc3F)n2)cn1
Agent: Cl
Product: O=C(Cn1cc(Nc2ncc(F)c(NCc3c(F)cc(F)cc3F)n2)cn1)NC1CC1
Temperature: 140 °C

Procedure:
Ethyl 2-(4-((5-fluoro-4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetate I-54 (97 mg, 0.23 mmol, prepared by Procedure B), cyclopropylamine (0.5 mL, 7.2 mmol) and conc. hydrochloric acid (2 drops) were mixed in a vessel and then heated in a microwave reactor at 140° C. for 30 min. The resulting precipitate was collected, triturated in ethyl acetate, filtered, washed with ether and methanol to afford N-cyclopropyl-2-(4-((5-fluoro-4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide I-4 (24 mg, 0.05 mmol) as a white solid. LC-MS (Method B), RT=5.88 min. (ES+) 436.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]=[C:11](C(Cl)(Cl)Cl)[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+]>C(O)C>[C:1]1([CH2:7][C:8]2[NH:12][C:11](=[O:17])[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: ClC(Cl)(Cl)c1nc(Cc2ccccc2)no1
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(Cc2ccccc2)no1

Procedure:
60 g. (0.22 moles) of 3-(phenylmethyl)-5-trichloromethyl-1,2,4-oxadiazole is dissolved in 100 ml. of ethanol. The solution is stirred and 132 ml. (0.264 mole) of 2N sodium hydroxide solution are added dropwise. The temperature of the mixture rises to about 40°. After the addition has been completed, the mixture is stirred for an additional 30 minutes and then concentrated in a rotary evaporator. The residue is treated with water, filtered and the filtrate is acidified with 2N hydrochloric acid. The crystals are filtered under suction, and purified by dissolving in sodium bicarbonate solution, filtering and precipitating with dilute hydrochloric acid. 29.7 g. of 3-(phenylmethyl)-1,2,4-oxadiazol-5-(4H)-one are obtained, m.p. 114°-116°.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11]>C(O)C>[CH2:8]([NH:12][C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Cc1nsc(Cl)n1
Reactant: CCCCN
Solvent: CCO
Product: CCCCNc1nc(C)ns1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-3-methyl-1,2,4-thiadiazole (27 g, 0.20 mol) was dissolved in 200 ml ethanol and, under cooling in an ice bath, added to an ethanolic solution of butylamine (44 g, 0.60 mol), stirred at room temperature overnight and evaporated to small bulk. Upon addition of ether a white precipitate of butylamine hydrochloride formed which was filtered off. The yellow filtrate was washed with water, dried over magnesium sulphate, filtered and evaporated to dryness to yield a yellow oil which was distilled under vacuum to give 5-butylamino-3-methyl-1,2,4-thiadiazole as a pale yellow liquid. Yield 29.9 g, (87.2%), b.p. 101°-102° C./0.14 mmHg.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:7]=1.C(S(C1[CH:26]=[CH:27][C:28](OC)=[C:29]([C:31]2[NH:32][CH:33]=CC=2)C=1)(=O)=O)C>>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:13]2[NH:14][C:15]([CH2:33][N:32]3[CH2:31][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][CH:17]=2)[CH:5]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(OC)c(-c2ccc[nH]2)c1
Reactant: CCS(=O)(=O)c1cc(Br)c(OC)c(-c2ccc[nH]2)c1
Product: CCS(=O)(=O)c1cc(Br)c(OC)c(-c2ccc(CN3CCCCC3)[nH]2)c1

Procedure:
This compound was prepared by a method analogous to that used to prepare example 2, but using 2-(3-bromo-5ethylsulphonyl-2-methoxy-phenyl)-1H-pyrrole (prepared according to the method of Kruse et al., [Heterocycles, 26,3141, 1987] from the corresponding acid chloride) in place of 2-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole. NMR δ(CDCl3) 1.30-1.70 (9H, m), 2.40 (4H, m), 3.15 (2H, q, J=7 Hz), 3.50 (2H, s), 3.80 (3H, s), 6.10 (1H, t, J=2 Hz), 6.60 (1H, t, J=2 Hz), 7.80 (1H, d, J=1 Hz), 8.00 (1H, d, J=1 Hz), 9.9 (1H, s).
Reaction SMILES: [CH3:1]I.[CH2:3]([C:7]1[C:8](=[O:14])[NH:9][C:10](=[S:13])[NH:11][CH:12]=1)[CH2:4][CH2:5][CH3:6].[OH-].[Na+]>O.C(O)C>[CH2:3]([C:7]1[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:1])=[N:11][CH:12]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1c[nH]c(=S)[nH]c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1cnc(SC)[nH]c1=O
Yield: 25.2 %

Procedure:
Methyl iodide (2.74 g) was added to a stirred solution of 5-butyl-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone (3.5 g) and sodium hydroxide (0.78 g) in water (10 ml) and ethanol (20 ml) at room temperature and heated at 70° for 45 minutes. The solid which separated on standing was filtered and washed with ethanol and water to give the title compound (0.95 g) m.p. 138°-140.5°.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>C1COCC1.C(OCC)(=O)C>[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([NH:4][CH2:3][CH2:1][OH:2])=[O:9]
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of ethanolamine (1.10 g, 15.8 mmol) in THF at 0° C. under N2 was added 2,4-difluorobenzoyl chloride (500 mg, 2.83 mmol). The reaction mixture was stirred at 0° C. for 4 h, then diluted with ethyl acetate (100 mL) and washed with 1 N HCl (50 mL), saturated NaHCO3 (50 mL), and saturated NaCl (50 mL). The organic solution was dried over MgSO4 and concentrated in vacuo to yield 2,4-difluoro-N-(2-hydroxyethyl)benzamide as a white solid (495 mg, 87%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([C:46]([F:49])([F:48])[F:47])[CH:40]=3)=[O:37])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:36]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([NH:25][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]6[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]6)=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)[S:27][C:28]=3[CH:34]=2)=[O:37])=[CH:40][C:41]=1[C:46]([F:48])([F:47])[F:49]
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Product: COc1cc2c(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)cc4s3)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-(2-{6-methoxy-7-[3-(4-methylpiperazin-1-yl)-propoxy]quinazolin-4-ylamino}benzothiazol-6-yl)urea was prepared from 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)-propoxy]quinazoline (Intermediate 6, 38.6 mg, 0.11 mmol) and 1-(2-aminobenzothiazol-6-yl)-3-(4-chloro-3-tri-fluoromethylphenyl)urea (Intermediate 3, 42.5 mg, 0.11 mmol) according to GP 1. The crude product was isolated by centrifugation and washed thoroughly with dioxane, methanol, water, and finally methanol. After drying, tetrahydrofuran was added (0.5 mL) and the mixture was filtered through glass wool to obtain pure product (pale yellow solid, 36 mg, 52 μmol, 47%). LC/ESI-MS: m/z=701 [M(35Cl)+H]+; m/z=699 [M(35Cl)−H]−; Rt=2.88 min.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]=[C:11]([C:14]([F:17])([F:16])[Cl:15])[N:12]([OH:13])[C:5]=12)([O-])=O.[NH2:18][C:19]1C=CN=C2N=C(C(F)(F)Cl)N(O)C=12.N([O-])=O.[Na+].[C-]#N.[Na+]>>[C:19]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]=[C:11]([C:14]([F:17])([F:16])[Cl:15])[N:12]([OH:13])[C:5]=12)#[N:18]
Reactant: Nc1ccnc2nc(C(F)(F)Cl)n(O)c12
Reactant: O=[N+]([O-])c1ccnc2nc(C(F)(F)Cl)n(O)c12
Agent: O=N[O-]
Agent: [C-]#N
Agent: [Na+]
Product: N#Cc1ccnc2nc(C(F)(F)Cl)n(O)c12

Procedure:
7-Chloro-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo-(4,5-b)pyridine is reacted with ammonium hydroxide to obtain 7-amino-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine which is oxidized to the corresponding 7-nitro-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine. Also, the 7-amino-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine is treated with sodium nitrite and subsequently sodium cyanide to obtain the corresponding 7-cyano-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine. On treatment with 70 percent sulphuric acid the corresponding 7-carboxy-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine is prepared. On further treatment with SF4 and HF, there is obtained 7-(trifluoromethyl)-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc2c(c1)OCO2

Procedure:
To a suspension of 3,4-methylenedioxyphenylacetic acid (569 mg, 3.16 mmol) in chloroform (6 ml) was added thionyl chloride (1.2 ml). The mixture was refluxed for about 3 hours, and was evaporated. Toluene was added to the residue and the mixture was evaporated to remove the excess of thionyl chloride. To the residue was added dichloromethane (3 ml) to give a dichloromethane solution of 3,4-methylenedioxyphenylacetyl chloride. To an ice-cold mixture of 2-amino-4-(4-piperidinyl)quinazoline (600 mg, 2.63 mmol) and triethylamine (319 mg, 3.16 mmol) in dichloromethane (16 ml) was added dropwise the solution of 3,4-methylenedioxyphenylacetyl chloride prepared above under a nitrogen atmosphere. The mixture was stirred for about two hours and to the reaction mixture was added dichloromethane and saturated sodium hydrogencarbonate aqueous solution followed by extraction. The organic layer was washed with water, and then dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). Crystallization from methanol gave the titled compound (617 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:41]([CH2:43][NH2:44])[OH:42]>CCOC(C)=O.C1COCC1>[OH:42][CH2:41][CH2:43][NH:44][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:27])([CH3:28])[C:24]1([CH3:26])[CH3:25])=[O:21])=[O:18]
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)NCCO)cc23)C1(C)C
Yield: 46 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and ethanolamine (21 μL, 0.34 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (51 mg, 0.12 mmol, 46% yield). 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.27 (s, 12H), 1.30-1.45 (m, 4H), 2.05-2.19 (m, 1H), 2.23 (s, 1H), 3.22 (dt, J=11.1, 3.2 Hz, 2H), 3.31-3.39 (m, 2H), 3.52 (q, J=6.0 Hz, 2H), 3.83 (d, 2H), 4.17 (d, J=7.1 Hz, 2H), 4.70 (t, J=5.6 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H), 8.35 (t, J=5.8 Hz, 1H), 8.38 (s, 1H), 8.74 (d, J=1.4 Hz, 1H); MS (DCI/NH3) m/z 427 (M+H)+; Anal. Calculated for C25H34N2O4.0.3H2O: C, 69.51; H, 8.07; N, 6.49. Found: C, 69.36; H, 7.88; N, 6.27.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[C:6]4[CH:16]=[CH:17][C:3]([Cl:2])=[CH:4][C:5]=4[O:9][N:8]=3)[CH2:15][CH2:14]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4cc(Cl)ccc34)CC2)CC1

Procedure:
Prepared as described for intermediate F (example 1) from a mixture 6-Chloro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride (0.942 g, 4 mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.06 g, 4 mmol) and sodium triacetoxyborohydride (1.51 g, 7 mmol) in 1,2 dichloroethane (9.8 mL) The product fractions were concentrated to give 1.2 g (2.6 mmol, 64.3% yield) of a light brown solid. MS (m/e): 462.4 (M+H+).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19]C1C=CC=CC=1)[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:29])=O>>[Cl:29][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC
Yield: 90 %

Procedure:
Dimethylformamide (0.2 ml) was added dropwise to a solution of 6-methoxy-7-benzyloxy-3,4-dihydroquinazolin-4-one (5.00 g, 17.9 mmol) in thionyl chloride (100 ml) and the reaction was heated at reflux for 1 hour. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (3×50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and water (100 ml) and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6,7-dimethoxyquinazoline (4.80 g, 90% yield) as a pale brown solid:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:41])[C@:34]([OH:40])([CH3:39])[C:35]([F:38])([F:37])[F:36].[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:30])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:41])[C@:34]([OH:40])([CH3:39])[C:35]([F:38])([F:37])[F:36]
Reactant: Nc1ccccc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)Nc3ccccc3)cc2)cc1Cl)C(F)(F)F
Reaction time: 144 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.195 g) was added to a solution of 4-(dimethylamino)pyridine (0.25 g), (R)-N-[2-chloro-4-(4-carboxyphenyl-sulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 121) (0.317 g) and aniline (0.075 ml) in DCM (30 ml) and the mixture was stirred for 6 days. Solvent was then removed by evaporation and the residue was partitioned between ethyl acetate (50 ml) and dilute aqueous hydrochloric acid (25 ml). The aqueous layer was further extracted with ethyl acetate (50 ml). The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography eluting with 40% ethyl acetate/hexane to give the title compound (0.1 79 g) as solid. NMR (CDCl3+DMSO-δ6): 1.59 (s, 3H), 7.03 (t, 1H), 7.25 (t, 2H), 7.48 (brs, 1H), 7.64 (d, 2H), 7.78 (dd, 1H), 7.92 (m, 3H), 8.06 (d, 2H), 8.56 (d 1H), 9.72 (s, 1H), 9.9 (s, 1H); MS (ESP−): 525.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: Cc1nc(C=O)cs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Cl)cs1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Anhydrous zinc chloride (0.133 g, 0.98 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (7 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.14 g, 0.49 mmol), acetic anhydride (0.138 mL, 1.46 mmol), and 2-methylthiazole-4-carboxaldehyde (0.185 g, 1.46 mmol in 4 mL of dioxane). The reaction was refluxed for 4 hours, at which time it was allowed to cool to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The mixture was repeatedly extracted with chloroform. The chloroform extracts were combined to form a chloroform layer which was washed with water and brine, dried over sodium sulfate and concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.16 g (57%) of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.