Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:36][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(NC3CCCCC3)nc2N1c1ccccc1
Yield: 96.1 %

Procedure:
A solution of 100 mg (0.22 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 300 μl (2.4 mmol) of cyclohexylamine in 2 ml of dichloromethane was stirred at room temperature overnight. The mixture was diluted with 10 ml of dichloromethane, washed with 10 ml of 2M hydrochloric acid and with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. 99 mg (96%) of 3-(2,6-dichlorophenyl)-7-cyclohexylamino-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one were isolated as a white foam of melting point 258-259° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:25]([OH:27])=[O:26])[CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:9]([CH3:28])[N:8]=[C:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:6]=2[CH:35]=1.[N+](=[CH2:38])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:25]([O:27][CH3:38])=[O:26])[CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH:9]([CH3:28])[N:8]=[C:7]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:6]=2[CH:35]=1
Reactant: CC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NN=C(CCCN1CCN(C)CC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: COC(=O)C(CCCN1CCN(C)CC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1C

Procedure:
In the manner given in Example 14, a solution of 7-chloro-2-[[1-carboxy-4-(4-methylpiperazino)butylidene]-hydrazino]-3-methyl-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-4-(4-methylpiperazino)butylidene]-hydrazino]-3-methyl-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2O)[NH:4][N:3]=1.CCN(C1C=CC=CC=1)CC.O(Cl)[Cl:24]>>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:24])[NH:4][N:3]=1
Reactant: Oc1ncnc2[nH]nc(Br)c12
Reactant: ClOCl
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncnc2[nH]nc(Br)c12
Temperature: 106 °C

Procedure:
3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate A) (15.08 g, 70.5 mmol) was suspended in 189 ml of phosphous oxychloride. Diethylaniline (19 ml, 119.4 mmol) was added and the resulting reaction mixture was heated to 106° C. for 2 hours. After cooling to room temperature, the solvent was removed and the resulting amber syrup was poured to 300 ml of ice-water. 20 minutes later, the aqueous layer was extracted with diethyl ether (500 ml×4). The combined organic layer was washed, dried and evaporated to give 6.87 g of 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine as light yellow solid. 1H NMR (DMSO) 8.857 (s 1H), 14.84 (bs, 1H); LC/MS (MH+=233).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14]([C:21]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([N:29]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:28]=2)=[O:22])=[CH:13]1)[CH3:11])(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:27]1[CH:28]=[C:23]([C:21]([C:14]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:12]([CH:10]([CH3:11])[CH2:9][OH:8])[CH:13]=2)=[O:22])[CH:24]=[N:25][CH:26]=1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cnccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of [1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]{5-[(diphenylmethylene)amino]pyridin-3-yl}methanone (Enantiomer 1, Preparation 33, 150 mg, 0.260 mmol) in DCM (5 mL) was added TFA (0.2 mL) and the reaction stirred at room temperature for 4 hours. The reaction was purified directly by preparative HPLC to afford the title compound (40 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1[O:21][CH3:22].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].[OH-].[K+]>CO>[CH2:23]([N:9]1[CH2:8][CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([O:19][CH3:20])[C:3]([O:21][CH3:22])=[C:2]([Br:1])[C:12]=2[CH2:11][CH2:10]1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1cc2c(c(Br)c1OC)CCNCC2c1ccccc1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCc2c(cc(OC)c(OC)c2Br)C(c2ccccc2)C1

Procedure:
A mixture of 4.9 g of 6-bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 ml of n-butyl bromide and 0.02 mol of potassium hydroxide is dissolved in 120 ml of dry methanol and refluxed for 48 hours. The reaction mixture is evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate is washed with water, dried and evaporated to give 3-n-butyl-6-bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:25]=[CH:24][C:16]([CH:17]([CH3:23])[CH2:18][C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:17]([CH3:23])[CH2:18][C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)=[O:9])=[CH:26][CH:27]=1)(=[NH:2])[NH2:3]
Reactant: COC(=O)CC(C)c1ccc(CCNC(=O)c2ccc(C(=N)N)cc2)cc1
Solvent: CO
Product: CC(CC(=O)O)c1ccc(CCNC(=O)c2ccc(C(=N)N)cc2)cc1
Reaction time: 8 h

Procedure:
113 mg of methyl rac-p-[2-(p-amidinobenzamido)ethyl]-β-methylhydrocinnamate were dissolved in methanol/2N sodium hydroxide solution and stored at room temperature overnight. The residue after removal of the solvent was dissolved in hot methanol, and ether was added. The crystals precipitated were filtered off with suction and dried over high vacuum, resulting in 52 mg of the sodium salt of rac-p-[2-(p-amidinobenzamido)ethyl]-β-methylhydrocinnamic acid. The melting point in dimethyl formamide was greater than 200° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][C:19](O)=[O:20])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][C:19]([Cl:26])=[O:20])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
In a dry flask, a solution of 15.32 g. (50 mmol.) of (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid in 100 ml. of benzene was heated under N2 to 50° C. as 21.15 ml. (0.25 mol.) of oxalyl chloride was added over 20 minutes. The solution was stirred at 50° C. for another 20 minutes, cooled and stripped of solvent to produce (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetyl chloride. To a solution of this acid chloride in 200 ml. of dry toluene was added 15 g. of sodium acetate and 1.5 g. of 10% by weight palladium on 90% by weight carbon and 0.30 ml. of quinoline. This mixture was hydrogenated in a Parr apparatus. After 12 hours, the uptake of H2 (about 55 mmole) had virtually ceased. The catalyst was removed by filtration and the filtrates were stripped of solvent. The residue was taken up in ether, washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate and stripped of solvent to give 15.4 g. of light yellow solid which was chromatographed on 1 kg. of 0.063-0.2 mm silica gel. Elution with 95:5 parts by volume benzene-ethyl acetate gave 11.0 g. of light yellow resin. The material from two such reactions was combined and crystallized from acetone-petroleum ether (b.p. 30°-60° C.) to give (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)-acetaldehyde as a white powder, sint 66.5° C., m.p. 68°-70° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:13])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CSc1ccc(CCl)cc1

Procedure:
To a stirred solution of 154 g (1 mol) of 4-methylmercaptobenzyl alcohol in 1 liter of dry benzene was added dropwise 80 mL 1.1 mol) of thionyl chloride. The mixture immediately turned blue. After the addition of the thionyl chloride was completed, the mixture was heated at reflux for 2 hours. After cooling the benzene and excess thionyl chloride were distilled at ambient pressure. The product was distilled in vacuo at 105° C. (0.5 mm), to yield 160 g (93%) of water clear liquid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][NH:21][CH:22]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43]([N:21]([CH2:20][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24][CH2:23]1)=[O:44]
Reactant: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 202 (42 mg, 81 mmol) is treated with acid chloride 8 (24 mg, 89 μmol) using Method D to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(N)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.532 g (4.5 mmol) 4-aminobenzonitrile is heated for 1.5 h at 90° C. The reaction mixture is then distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 and). 25:1). Title compound is obtained after crystallization of the product-containing fractions from dichloromethane and drying under HV (8 h, 90° C.); m.p. 228-230° C.; ESI-MS: (M+H)+=338.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([F:22])[CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=2[CH3:8])=[C:17]([F:22])[CH:16]=1
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Reactant: Nc1ccc(Br)cc1F
Product: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)O)cn(C)c1=O

Procedure:
The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 4-bromo-2-fluoroaniline instead of 2-fluoro-4-iodoaniline The title compound is used for the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:27]([OH:29])=[O:28])[C:5]2[C:10]([C:11]=1N=NC1C(C)=NN(C3C=CC=CC=3)C=1O)=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=O.[Na+].S(=O)(=O)(O)O>O>[OH:1][C:2]1[CH:3]=[C:4]([C:27]([OH:29])=[O:28])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nn(-c2ccccc2)c(O)c1N=Nc1c(O)cc(C(=O)O)c2ccccc12
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc2ccccc12
Reaction time: 1 h

Procedure:
A solution of the compound from example 14 b) (8.73 g; 0.042 mol.) in water (300 mL) was treated with 2M aqu. sulfuric acid (60.0 mL) to precipitate the free acid as a fine powder. This suspension was then stirred and cooled to 10° then slowly treated dropwise with a solution of sodium nitrite (3.03 g; 0.044 mol.) in water (30.0 mL). After 30 min. at 10° the solution was added very slowly dropwise to a refluxing solution of 40% aqu. sulfuric acid (1 L). Complete addition took ˜1 h. After complete addition the mixture was heated under reflux for a further 15 min. then quickly hot-filtered through a plug of glass wool to remove insoluble, charred material. The filtrate was allowed to cool depositing the title compound (5.85 g; 74%) as yellow crystals. mp 210-212°. MS(ES) m/z 187 [M−H].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:12]([O:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Yield: 84.2 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (1 g), pyrrolidin-3-ylcarbamic acid tert-butyl ester (1.2 g), potassium carbonate (1.79 g) and dimethyl sulfoxide (10 ml) were heated together at 80° C. under nitrogen for 15 h. The mixture was then cooled, diluted with ethyl acetate (200 ml), washed with 2N aqueous hydrochloric acid (200 ml), dried (MgSO4) then concentrated. Purification of the residue by silica gel chromatography (eluting with 20% ethyl acetate in isohexane) gave the subtitle compound (1.744 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[Cl:28][C:29]1[CH:34]=[C:33](F)[C:32]([F:36])=[CH:31][C:30]=1[S:37]([CH3:40])(=[O:39])=[O:38].O>CN1C(=O)CCC1>[Cl:28][C:29]1[C:30]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:31][C:32]([F:36])=[C:33]([CH:34]=1)[O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12]
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1Cl
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2cc(Cl)c(S(C)(=O)=O)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 115 °C
Yield: 49.5 %

Procedure:
Potassium carbonate (1.00 g) was added to a solution of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.41 g) and 1-chloro-4,5-difluoro-2-(methylsulfonyl)benzene (0.79 g) in NMP (20 mL). The mixture was heated to 115° C. for 3.5 hours and left to cool before being poured into water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organics were washed with water, brine and dried (MgSO4) before evaporation in vacuo. Chromatography on silica, eluting with 0 to 10% methanol in ethyl acetate, afforded the desired compound (0.86 g)
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:3]=1[O:4][C:5]1[N:6]=[C:7]([O:38][CH2:39][CH2:40][CH3:41])[C:8]2[N:13]=[C:12]([C:14]3[CH:35]=[C:34]([CH3:36])[C:17]([O:18][CH2:19][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[C:27]([O:29]C(C)(C)C)=[O:28])=[O:21])=[C:16]([CH3:37])[CH:15]=3)[O:11][C:9]=2[N:10]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:3]=1[O:4][C:5]1[N:6]=[C:7]([O:38][CH2:39][CH2:40][CH3:41])[C:8]2[N:13]=[C:12]([C:14]3[CH:35]=[C:34]([CH3:36])[C:17]([O:18][CH2:19][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[C:27]([OH:29])=[O:28])=[O:21])=[C:16]([CH3:37])[CH:15]=3)[O:11][C:9]=2[N:10]=1
Reactant: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)O)c(C)c3)nc12
Reaction time: 16 h

Procedure:
59 mg of tert-butyl(S)-1-(2-{4-[5-(2,5-difluorophenoxy)-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidine-2-carboxylate were dissolved in 1.2 ml of dichloromethane, and 0.5 ml of trifluoroacetic acid was added. After 16 h at room temperature, the mixture was concentrated under reduced pressure and freeze-dried. This gave 53 mg of the title compound.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4]CC1.C(OC(C)C)(OC(C)C)O[CH:11]([CH3:13])[CH3:12].C(O)(C)C.O.S([O-])(O)(=O)=O.[Na+]>>[CH:11]([O:8][C:1]1[CH2:7][CH2:6][CH2:5][CH:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: O=C1CCCCCC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC1=CCCC1
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a mixture of 56.0 grams (0.50 mol) of cycloheptanone, 107.0 grams (0.56 mol) of triisopropyl orthoformate and 44 grams of isopropanol (0.73 mol) in a 500 ml three-neck round bottom flask was added 2.8 grams (0.020 mol) of sodium hydrogensulfate monohydrate. Upon catalyst addition, the reaction temperature rose to 45° C., and was heated and maintained at 50° C. for about 5 hours. The progress of the reaction was monitored by GC until the ketone concentration was below 2%. The isopropanol and isopropyl formate by-products were removed by distillation under reduced pressure while the temperature of the reaction mixture was increased to a maximum of 60° C. The reaction mixture was cooled to room temperature and the pH value adjusted to about 7˜8 by adding 0.4 of gram potassium iso-propoxide. The mixture was then heated under reduced pressure to remove unreacted cycloheptanone and 1-isopropoxy-1-cyclopentene was isolated as a clear liquid at a yield of 60.1%. The purity of the product exceeded 98%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCNC[C@H]1C
Reaction time: 12 h

Procedure:
A solution of 2.05 g (R)-2-Methyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-ethyl ester in 15 ml dichloromethane was treated with 11.2 ml TFA and the resulting solution stirred for 12 h. The solvents were removed in vacuum and the crude hydrotrifluoroacetate transformed to the free amine by treatment with (Polystyrylmethyl)trimethylammonium bicarbonate in MeCN. Yield: 1.45 g.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:13](=[O:14])[N:12]2[C:7]([S:8][CH2:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[CH3:15].[BrH:16]>C(O)(=O)C>[BrH:16].[Br:16][CH2:2][CH2:3][C:4]1[C:13](=[O:14])[N:12]2[C:7]([S:8][CH2:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[CH3:15]
Reactant: Cc1nc2n(c(=O)c1CCO)CCCS2
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCBr)CCCS2
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 20 parts of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, 50 parts of acetic acid and 180 parts of a hydrobromic acid solution 67% in acetic acid was stirred and heated to reflux. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated and the solid residue was triturated in 2-propanone. The product was filtered off and dried, yielding 24 parts (100%) of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one monohydrobromide; mp. 215° C. (intermediate 168).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:25])=[C:20]([CH:24]=3)[C:21]([OH:23])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:27]O>O1CCOCC1>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:25])=[C:20]([CH:24]=3)[C:21]([O:23][CH3:27])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: Nc1ccc2ccc(S(=O)(=O)Nc3ccc(Cl)c(C(=O)O)c3)cc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 10.1 g (0.027 mol) of compound 133 dissolved in 250 mL of methanol was added 50 mL of 4 N HCl in dioxane. This solution was allowed to stir at ambient temperature for 18 hours. The reaction was incomplete, so it was heated at reflux for an additional 5 hours. Then, the volatiles were removed by rotary evaporation and the resulting solid was extracted with ethyl acetate and 0.4 N sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation to yield 8.71 g of compound 134.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([C:15]([CH3:19])([CH3:18])[CH:16]=O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:2])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C(C)(C)C=O)cc1Br
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC(C)(C)c1ccc(OC)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (7.71 g, 0.0215 mol) in dry THF (100 mL) was cooled to 0° C. under argon. n-BuLi (2.5M, 8 mL, 0.020 mol) was added slowly. The resulting clear orange solution of the ylide was stirred for another 15 min at 0° C. 2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionaldehyde (3.7 g, 0.014 mol) was dissolved in dry THF (50 mL) and added to ylide-solution. The mixture was stirred for 3 h/25° C. and the resulting suspension was quenched with MeOH (10 mL). The solvent was removed under reduced pressure and the crude product was purified by flash chromatography using n-heptane as eluent. Yield: 3.1 g (84%). GCMS: >99%