Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)C.[Na].O.Cl>C(O)C>[CH2:17]([O:16][C:14]([C:13]1[NH:12][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=2[C:4]=1[OH:3])=[O:15])[CH3:18]
Reactant: CCOC(=O)CNC1=C(C(=O)OCC)CCCC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2c(c1O)CCCC2
Reaction time: 3 h

Procedure:
294 g of 2-(ethoxycarbonylmethylamino)-cyclohexene-1-carboxylic acid ethyl ester in 400 ml of ethanol are added dropwise, under nitrogen, to a well-stirred solution of 35 g of sodium in 1.5 liters of ethanol. After the solution has boiled for three hours, it is cooled and 600 ml of water are then added, followed by 150 ml of concentrated hydrochloric acid. After the batch has stood for six hours at -10° C., 142 g of 3-hydroxy-4,5,6,7-tetrahydroindole-2-carboxylic acid ethyl ester, of melting point 94°-95° C., are filtered off.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:49]1[CH2:50][CH2:51][CH2:52][C@H:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48]1)(=[O:18])[CH3:16]
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC[C@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and acetyl chloride as the starting materials in 55% yield. LCMS for C26H29ClN7O2 (M+H)+: m/z=506.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:17][CH2:16]2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cncc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (4.8 g, 20.86 mmol) in DMF (100 mL) was added 60% NaH in mineral oil (1.1 g, 45.9 mmol), and the mixture was stirred at 0° C. for 15 min. A solution of 1,2-dibromoethane (3.92 g, 20.86 mmol) in DMF (20 mL) was added and the mixture was stirred at room temperature for 1 h. Two other portions of 60% NaH in mineral oil (200 and 450 mg) were added sequentially, until conversion was complete. The mixture was poured into EtOAc (1 L) and washed with water (60 mL), dried over Na2SO4 and concentrated in vacuo to give an oil which was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Trifluoromethoxybenzene boronic acid. MS (M+H) 437.1
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10](OCC)=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[O-2].[O-2].[Mn+4].O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Mn+4]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C=O)[nH]n1
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a mixture of ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (4.00 g, 20.4 mmol) and tetrahydrofuran (50 mL) was added lithium aluminum hydride (800 mg, 21.1 mmol) by small portions under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. Sodium sulfate decahydrate (7.6 g) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was concentrated and a mixture of the obtained residue, manganese dioxide (10 g, 115 mmol) and tetrahydrofuran (100 mL) was stirred at room temperature for 3 hr. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (2.13 g, yield 69%) as colorless crystals.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.CN(C=O)C.CCN(C(C)C)C(C)C.[CH2:30]([NH2:33])[C:31]#[CH:32].[H-].[Na+]>C(Cl)Cl.[Cl-].[NH4+].O.O1CCOCC1>[Br:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]1[O:10][C:31]([CH3:32])=[CH:30][N:33]=1
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: C#CCN
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cnc(-c2cccc(C)c2Br)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.679 mL, 9.30 mmol) was added to a solution of 2-bromo-3-methylbenzoic acid (2.0 g, 9.30 mmol) and DMF (0.072 mL, 0.930 mmol) in DCM (100 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 1 h and then cooled to 0° C. before DIPEA (3.25 mL, 18.60 mmol) followed by 2-propynylamine (0.766 mL, 11.16 mmol) were added. The resulting solution was stirred for 45 min at 0° C. The reaction mixture was diluted with saturated ammonium chloride and water and then extracted with EtOAc. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium bicarbonate, saturated sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material as a tan solid. The crude product was dissolved in dioxane (100 mL) and cooled to 0° C. Sodium hydride (0.409 g, 10.23 mmol) was added and the mixture was stirred at RT for 30 min before bringing to a reflux. After 5 h, the reaction is concentrated. The crude material was purified by silica gel chromatography to provide 2-(2-bromo-3-methylphenyl)-5-methyloxazole.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:3]1.CC1CCOC(C2C=CC(OC)=CC=2)C=1>>[CH3:1][C:2]1[CH2:3][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[O:5][CH2:6][CH:7]=1
Reactant: C=C1CCOC(c2ccc(OC)cc2)C1
Agent: COc1ccc(C2C=C(C)CCO2)cc1
Product: COc1ccc(C2CC(C)=CCO2)cc1
Yield: 35 %

Procedure:
The method of claim 6 wherein the mixture of 3-10% tetrahydro-4-methylene-2-(4-methoxyphenyl)-2H-pyran, 35-55% 5,6-dihydro-4-methyl-2-(4-methoxyphenyl)-2H-pyran, and 35-55% 3,6-dihydro-4-methyl-2-(4-methoxyphenyl)-2H-pyran is provided at a level of from about from about 0.2 to about 25 weight percent of the fragrance composition.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[O:87]=[C:88]1[N:92]([CH2:93][C:94]([OH:96])=O)[C@@H:91]([C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)[CH2:90][O:89]1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:96])[CH2:93][N:92]1[C@@H:91]([C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)[CH2:90][O:89][C:88]1=[O:87])[CH2:19][CH2:18]2
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3C(=O)OC[C@@H]3c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (S)-(+)-2-oxo-4-phenyl-3-oxazolidineacetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 733.5 (M+H)+, 2.25 min (method 6). 1H NMR (400 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.3 Hz, 2H), 7.47-7.39 (m, 3H), 7.37-7.32 (m, 2H), 7.20 (d, J=8.3 Hz, 2H), 6.60 (s, 1H), 5.28 (d, J=4.5 Hz, 1H), 5.04 (t, J=8.3 Hz, 1H), 4.75 (t, J=8.9 Hz, 1H), 4.71 (s, 1H), 4.61 (br. s., 1H), 4.25-4.19 (m, 1H), 4.04 (d, J=16.3 Hz, 1H), 3.40 (d, J=16.3 Hz, 1H), 2.65-2.59 (m, 1H), 2.47 (dt, J=4.8, 11.0 Hz, 1H), 2.37 (dd, J=8.2, 11.7 Hz, 1H), 2.11 (dd, J=6.3, 17.1 Hz, 1H), 1.84-1.70 (m, 4H), 1.69 (s, 3H), 1.66-1.59 (m, 1H), 1.58-1.40 (m, 7H), 1.39-1.22 (m, 6H), 1.09 (br. s., 1H), 1.07 (s, 3H), 1.00 (s, 6H), 0.95 (s, 3H), 0.94 (br. s., 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C@H:4]1[O:9][CH:8]([OH:10])[CH2:7][C@H:6]([OH:11])[CH2:5]1.C(=O)([O-])[O-].[Ba+2].BrBr>O>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C@H:4]1[O:9][C:8](=[O:10])[CH2:7][C@H:6]([OH:11])[CH2:5]1
Reactant: COC(OC)[C@@H]1C[C@@H](O)CC(O)O1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: O
Product: COC(OC)[C@@H]1C[C@@H](O)CC(=O)O1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a solution of 1.4 g of (4R,6S)-6-(dimethoxymethyl)-tetrahydro-2H-pyran-2,4-diol (I′) in 100 mL of water, 2.4 g of barium carbonate and 0.5 mL of bromine at 0° C. are added. After 3 hours of stirring at 0-5° C., the product II′ is extracted three times with 300 mL of ethyl acetate. Finally ethyl acetate is distilled off. The residue is flash chromatographed (DIPE/acetonitrile 2/1). The solvents are distilled off to get the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.O[C:16]1[N:21]2[N:22]=[CH:23][CH:24]=[C:20]2[N:19]=[C:18]([S:25][CH3:26])[C:17]=1[C:27]#[N:28]>>[Cl:3][C:16]1[N:21]2[N:22]=[CH:23][CH:24]=[C:20]2[N:19]=[C:18]([S:25][CH3:26])[C:17]=1[C:27]#[N:28]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2ccnn2c(O)c1C#N
Solvent: CN(C)c1ccccc1
Product: CSc1nc2ccnn2c(Cl)c1C#N
Temperature: 110 °C
Yield: 80 %

Procedure:
Under nitrogen gas atmosphere, phosphorous oxychloride (9.4 mL, 101.3 mmol) and dimethylaniline (2.6 mL, 20.3 mmol) was added successively to the intermediate, 7-hydroxy-5-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile, prepared above (4.1 g, 19.7 mmol). The mixture was heated at 110° C. for 4 hours then excess POCl3 was removed under vacuum. The residue was made basic with 3N NaOH solution (pH=9-10) and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by recrystallization from ethyl acetate hexanes to provide the product, 7-chloro-5-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (80% yield). LCMS (M+1=225)
Reaction SMILES: NC(C)C(O)=O.[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([CH2:15][C:16]2[CH:17]=[C:18]([O:58][CH3:59])[C:19]([O:56][CH3:57])=[C:20]([CH:22]=[CH:23][C:24]([N:26]3[N:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]3[C:36]3[CH:55]=[CH:54][C:39]([CH2:40][O:41][C:42](=[O:53])[CH:43]([NH:45]C(OC(C)(C)C)=O)[CH3:44])=[CH:38][CH:37]=3)=[O:25])[CH:21]=2)=[CH:10][N:9]=1.CS(O)(=O)=O>C(O)C(F)(F)F>[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([CH2:15][C:16]2[CH:17]=[C:18]([O:58][CH3:59])[C:19]([O:56][CH3:57])=[C:20]([CH:22]=[CH:23][C:24]([N:26]3[N:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]3[C:36]3[CH:37]=[CH:38][C:39]([CH2:40][O:41][C:42](=[O:53])[CH:43]([NH2:45])[CH3:44])=[CH:54][CH:55]=3)=[O:25])[CH:21]=2)=[CH:10][N:9]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(C=CC(=O)N2N=Cc3ccccc3C2c2ccc(COC(=O)C(C)NC(=O)OC(C)(C)C)cc2)c1OC
Agent: CC(N)C(=O)O
Agent: CS(=O)(=O)O
Solvent: OCC(F)(F)F
Product: COc1cc(Cc2cnc(N)nc2N)cc(C=CC(=O)N2N=Cc3ccccc3C2c2ccc(COC(=O)C(C)N)cc2)c1OC
Yield: 58.1 %

Procedure:
Preparation of 2-amino-propionic acid 4-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl -acryloyl}-1,2-dihydro-phthalazin-1-yl)-benzyl ester ##STR16## A solution of 130 mg of 2-tert-butoxycarbonylamino-propionic acid 4-(2-(3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-acryloyl)-1,2-dihydro-phthalazin-1-yl)-benzyl ester in 20 ml of trifluoroethanol is treated with 18 μl of methanesulphonic acid at room temperature over one hour. The reaction solution is concentrated, the residue is taken up in ethyl acetate and filtered. The crystals are dissolved in 5 ml of water and treated with 20 ml of pH 7 buffer. The suspension obtained is suction filtered. There are obtained 65 mg of 2-amino-propionic acid 4-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-acryloyl)-1,2-dihydro-phthalazin-1-yl)-benzyl ester, MS (ISP): 622.3 (M+H)+
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:7]1=[NH:19].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C1(OC)C=CC=CC=1.O>[N+:16]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH2:19])=[N:6][CH:15]=[CH:14]2)([O-:18])=[O:17]
Reactant: COc1ccc(Cn2ccc3cc([N+](=O)[O-])ccc3c2=N)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc([N+](=O)[O-])ccc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a solution of Intermediate 1B (11.9 g, 35 mmol) in anisole (24 mL) was added TFA (24 mL). The reaction mixture was stirred at 90° C. for 6 h and the solvent was removed under reduced pressure. The residue was suspended in MeOH (50 mL) and then treated with NaHCO3 (3.3 g, 39 mmol) in water (200 mL). The mixture was stirred at rt for 15 min and the pH was checked to be 9-10. The precipitate was collected by filtration and washed with water to afford Intermediate 1C (6.0 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J=5.7 Hz, 1H), 7.36 (s, 2H), 7.95 (d, J=5.7 Hz, 1H), 8.15 (dd, J=9.2, 2.6 Hz, 1H), 8.43 (d, J=9.2 Hz, 1H), 8.67 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:33]1[N:34]([C:38]2[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=2[C:40](O)=[O:41])[N:35]=[CH:36][CH:37]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:40]([C:39]4[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=4[N:34]4[N:35]=[CH:36][CH:37]=[N:33]4)=[O:41])[CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1cnc(C)c(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(C)c(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3,6-dimethyl-pyrazin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 10) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid and DCM in place of DMF. DCM was used in place of DMF. MS (ESI) mass calcd. For O21H23N7O, 389.46; m/z found 390.1 [M+H]+. 1H NMR (CDCl3): 8.03-7.91 (m, 1H), 7.81-7.64 (m, 2H), 7.54-7.20 (m, 3H), 6.99-6.87 (m, 1H), 4.87-3.93 (m, 4H), 3.78-3.48 (m, 2H), 3.29-2.75 (m, 2H), 2.39-2.29 (m, 4H), 2.06-2.02 (m, 4H).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[C:16]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:15]=2)[CH2:9][CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[C:16]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:15]=2)[CH2:9][CH2:8]1
Reactant: COc1ccc2nc(C=Cc3ccccn3)nc(N[C@H]3CC[C@@H](CNC(=O)C(F)(F)F)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2nc(C=Cc3ccccn3)nc(N[C@H]3CC[C@@H](CN)CC3)c2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of cis-4-trifluoroacetylaminomethyl-N-{2-[2-(2-pyridyl)ethenyl]-6-methoxyquinazolin-4-yl}cyclohexylamine in 45 mL of methanol and 5 mL of water was combined with 414 mg of potassium carbonate, and stirred at room temperature for 15 hours. The reaction solution was combined with water, extracted with chloroform, and then dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol:aqueous ammonia=100:10:1) to obtain 120 mg of the desirable compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:16])=[C:11]([N:13]=[C:14]=[S:15])[CH:12]=1>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:16])=[C:11]([NH:13][C:14](=[S:15])[NH:1][CH2:2][C:3]([NH2:5])=[O:4])[CH:12]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: NCC(N)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
Glycinamide (10.08 g) and 5-chloro-2-methylphenyl-isothiocyanate (23 g) were heated at reflux in chloroform (300 mL) for 30 minutes. The mixture was then stirred at ambient temperature for 3 hours. The precipitated solid was collected by filtration, washed with chloroform and air dried to give 2-[3-(5-chloro-2-methylphenyl)thioureido]-acetamide (28.5 g), m.p. 162°-164° C. Mass spectrum (El, M.+) m/z 257/259. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.46 (s, 1H), 7.83 (s, 1H), 7.51 (d, 2H), 7.24 (d, 1H), 7.24 (d, 1H), 7.18 (d, 1H), 7.15 (m, 2H), 4.06 (d, 2H), and 2.16 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2/[CH:13]=C/C.[O:16]=[O+][O-].CSC>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[O:16]
Reactant: C/C=C/c1cccc2c(=O)cc(C)oc12
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(=O)c2cccc(C=O)c2o1
Temperature: -60 °C

Procedure:
18.5 g (62.8 mmol) of 2-methyl-8-[(1E)-prop-1-en-1-yl]-4H-chromen-4-one are dissolved in 400 ml of dichloromethane and cooled to −60° C. Ozone is passed into the reaction solution for 30 min. Dimethyl sulfide is then added to the reaction mixture. After warming to room temperature, the solvent is removed in vacuo, and the residue is slurried in a little methanol. The solid remaining after filtration is recrystallized from diethyl ether. 9.1 g (77.4% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[Li+].[CH3:17][CH:18]([N-]C(C)C)C.C(I)C>C1COCC1>[CH2:17]([CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[C:11]([OH:13])=[O:12])[CH3:18]
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(Cc1cccc(C(F)(F)F)c1)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 eq. of 3-(3-trifluoromethylphenyl)propionic acid was converted, in THF and at -78° C., into the dianion using 2 eq. of LDA (stirring for 30 min. at -78° C., then 30 min. at RT). 2 eq. of ethyl iodide were then added at -78° C. and the mixture was subsequently stirred at RT. Acidic working-up using 2N HCl and purification by chromatography yielded 2-ethyl-3-(3-trifluoromethylphenyl)-propionic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OC)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27].[H-].[Na+].C([Li])CCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]2([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[O:18][C:24](=[O:29])[CH:25]=[C:26]([OH:27])[CH2:28]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2cccc(OCc3ccccc3)c2)(C2CCCC2)O1

Procedure:
The title compound was prepared as described in General Method 6 using 3-(3-benzyloxy-phenyl)-1-cyclopentyl-propan-1-one (3.3 g, 11.3 mmol) from Example YYYY, 2.45 mL (22.7 mmol) of methyl acetoacetate, 0.93 g (23.2 mmol) of 60% NaH dispersion in mineral oil, 14.5 mL (1.6 M, 23.2 mmol) of n-butyllithium and 40 mL of THF. The reaction mixture was quenched with 5 mL HOAc and the mixture was worked up in the normal manner.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:17][C:16]([S:18](O)(=[O:20])=[O:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1.C1C=CC=CC=1.S(Cl)([Cl:34])=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:17][C:16]([S:18]([Cl:34])(=[O:20])=[O:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1

Procedure:
5-(1-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonic acid (˜3.2 mmol from previous step) was combined with benzene (5.0 mL) in a reaction vial. This mixture was treated with thionyl chloride (5.0 mL, 69 mmol) and a catalytic amount of dimethylformamide (0.1 mL). The reaction was then heated to reflux in an oil bath. After refluxing for 1 hour the reaction mixture was concentrated under reduced pressure to afford a yellow oil that partially solidified under reduced pressure. This crude material was purified by flash column chromatography eluting with a gradient from 10% to 30% EtOAc/hexane. Product-containing fractions were collected and concentrated to afford 5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonyl chloride as a pale yellow oil. The mostly pure material was carried on to subsequent transformations without further purification.