Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][C@@H:9]([CH3:11])[C@:8]([C:13]#[CH:14])(O)[C:7]([CH3:16])([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].O>CC1C=CC=CC=1C.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:4][C@H:5]1[CH2:6][C:7]([CH3:15])([CH3:16])[C:8]([C:13]#[CH:14])=[C:9]([CH3:11])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: C#C[C@]1(O)[C@H](C)C[C@@H](OC(C)=O)CC1(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: C#CC1=C(C)C[C@@H](OC(C)=O)CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
121.6 g of crude (1R,4S,5R)-4-ethynyl-4-hydroxy-3,3,5-trimethylcyclohexyl acetate (prepared according to Example 9) were dissolved in 1 l of o-xylene under argon in a sulphonation flask having a water separator. The mixture was treated with 7.9 g of copper(II)sulphate and boiled and stirred intensively for 2 hours under reflux and with the separation of water. The reaction mixture was subsequently cooled to room temperature and the insoluble copper sulphate was filtered off (rinsing with 400 ml of hexane). The filtrate was washed with 400 ml of water and with 400 ml of semi-saturated sodium bicarbonate solution. The wash solutions were back-extracted twice with 300 ml of hexane each time. The organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated to a volume of about 200-300 ml in a rotary evaporator at 80 Torr and 40°-60° C. bath temperature. Distillation of the residual xylene solution in a high vacuum gave at about 83° C./0.19- 0.09 Torr 96.5 g of (R)-4-ethynyl-3,5,5-trimethyl-3-cyclohexen-1-yl acetate (purity 98.1%) as a colourless oil; boiling point 78°-82° C./0.14 Torr. The chemical yield amounted to 93% based on (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone.
Reaction SMILES: N1C=CC=CC=1.[OH-].[Na+].Cl.C(O)C.[CH3:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([NH2:25])=[O:24])=O)=[CH:16][CH:15]=1>>[CH3:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)Nc2ccccc2C(N)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Temperature: 0 °C
Yield: 93.1 %

Procedure:
A mixture of 11 ml of pyridine in 340 ml of 2 normal aqueous sodium hydroxide was heated to the reflux temperature and to the hot solution was added in one portion 16.3 g of 2-(4-methylbenzamido)benzamide. The mixture was maintained at reflux temperature for 15 minutes, then poured into 1000 ml of ice. The cold mixture was acidified with concentrated hydrochloric acid and the precipitate was cooled to give 14.1 g of white 2-(4-methylphenyl)-quinazolin-4(3H)-one, m.p. 242°-243.5° (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:22]([N:23]([CH3:25])[CH3:24])=[CH:21][C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH2:17])=[S:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.ClC1C(N(C)C)=CC2N=[C:32](C3C=C(C=CC=3)C#N)[CH2:33][C:34](=[O:36])NC=2C=1.C[Si](C)(C)S[Si](C)(C)C.C[O-].[Na+]>CN1CCN(C)C1=O.O>[Cl:1][C:2]1[C:22]([N:23]([CH3:25])[CH3:24])=[CH:21][C:5]2[N:6]=[C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[C:14]([C:15]4[S:16][CH:32]=[C:33]([CH2:34][OH:36])[N:17]=4)[CH:13]=3)[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[Cl:1][C:2]1[C:22]([N:23]([CH3:25])[CH3:24])=[CH:21][C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH2:17])=[S:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C#N)c1)=N2
Agent: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(N)=S)c1)=N2
Agent: C[O-]
Agent: C[Si](C)(C)S[Si](C)(C)C
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2
Reaction time: 0.25 h

Procedure:
The title compound was prepared from 3-(7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-thiobenzamide {prepared from 3-(7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4] diazepin-2-yl)-benzonitrile (Example 1) as follows: To a solution of hexamethyldisilthiane (0.55 mL, 2.6 mmol) in 1,3-dimethyl-2-imidazolidinone (2.6 mL) was added at 20° C. sodium methoxide (0.13 g, 2.5 mmol). The mixture was stirred for 15 min. and the blue solution formed was then added to a solution of 3-(7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 1) (0.34 g, 1.0 mmol) in 1,3-dimethyl-2-imidazolidinone (2 mL). The mixture was stirred for 3 h at 20° C. and then poured into water. The precipitate was isolated by filtration and triturated with acetone to give 3-(7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-thiobenzamide (0.35 g) as yellow solid, mp 234° C. dec.MS (ISP) 373.2 [(M+H)+].} (0.71 g, 1.9 mmol), 1,3-dichloro-2-propanone (0.36 g, 2.85 mmol) and sodium bicarbonate (0.24 g, 2.85 mmol) in 1,4-dioxane (15 mL) was heated to 60° C. for 48 h. The clear solution was evaporated in vacuum. The a solution of the residue in 1,4-dioxane (5 mL) was added 2N KOH (3.8 mL) and the mixture was stirred at 20° C. for 1 h. Water (100 mL) was added and the mixture was stirred for 0.5 h.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([N:35]([CH3:34])[C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)C4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methylcyclohexylamine. ES-MS m/e (%): 482 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.Cl.[NH2:14][OH:15]>CCO.[OH-].[Na+]>[OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[N:14][OH:15])[CH2:3]1)[CH2:9]2
Reactant: NO
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=C1C2CC3CC1CC(O)(C3)C2
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
5-Hydroxy-2-admantanone (15 g, 90.2 mmol, CAS #: 20098-14-0, purchased from TCI) was dissolved in EtOH (100 mL) and added to a solution of hydroxylamine hydrochloride (10 g, 143.9 mmol) in 1N NaOH (80 mL). The mixture was heated at 100° C. for 2 hours. The EtOH was evaporated, and water and dichloromethane were added. The resulting mixture was stirred for 10 min and then filtered. The solid was collected. The resulting mixture was separated. The aqueous layer was further extracted twice with dichloromethane. The combined organic phases were concentrated under high vacuum. The resulting residue was combined with the solid from the filtration. Crystallization from EtOAc gave 5-hydroxy-adamantan-2-one oxime (12 g, 73%). Mass spectrum: m/z: 182 (M+1).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[NH4+:11].C([O-])=O.C(O)(=O)C(C)=O.N>O>[NH2:11][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: [NH4+]
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: CC(=O)C(=O)O
Agent: N
Agent: O=C[O-]
Solvent: O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
0.16 mmol of keto glutaric acid whose R1 is (CH2)2COOH and R2 is H in FIG. 2(a) and 3.2 mmol of formate ammonium were poured into 3 mL of water so as to have the pH 4.5. 0.2 μmol of (η5-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl) aqua complex was added to the pyruvic acid aqueous solution, and the resulting mixture was reacted at 80° C. under argon atmosphere for an hour. After completion of the reaction, the resulting product was analyzed by 1H NMR. In isolation of the product, the reaction solution was condensed, and the condensed residue was dissolved in water, and the resulting water was made to pass through a cation exchange resin (DOWEX 50W-X2). After flowing 50 mL of water, 200 mL of 0.1M aqueous ammonia was flown, and the solution was condensed to give glutamic acid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=[C:19]([CH:28]=O)[CH:18]=1>>[CH3:16][C:17]1[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:20]=[C:19]([CH2:28][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:18]=1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: Cc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1-c1ccccc1
Yield: 46.9 %

Procedure:
Compound 2 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: BrC1C(Br)=C([C:12]([O:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19](Br)[C:18]=2Br)=[O:16])=[O:13])C2C(C=1)=CC=CC=2>CCOCC>[CH:23]1[CH:22]=[C:21]2[C:26]3=[C:25]([C:12]([O:14][C:15](=[O:16])[C:17]3=[CH:18][CH:19]=[CH:20]2)=[O:13])[CH:24]=1
Reactant: O=C(OC(=O)c1c(Br)c(Br)cc2ccccc12)c1c(Br)c(Br)cc2ccccc12
Solvent: CCOCC
Product: O=C1OC(=O)c2cccc3cccc1c23
Temperature: 25 °C

Procedure:
The following morning thin-layer chromatography showed only a trace presence of the dibromonaphthalic anhydride. The reaction mixture was cooled to room temperature followed by the addition of 350 ml of ether. The triethylamine hydrobromide byproduct was removed by filtration. The filtrate was concentrated on the rotary evaporator, to give the diphenylethynyl derivative of the 1,8-naphthalic anhydride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[S:11][CH:12]=1.[Cl:24]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CN(C=O)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Cl:24][C:12]1[S:11][C:10]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:9][C:8]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccncc1-c1csc(-c2cccc(C(=O)N(C)C)c2)n1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1nc(-c2cccc(C(=O)N(C)C)c2)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 3-[4-(4-methylpyridin-3-yl)-1,3-thiazol-2-yl]-N,N-dimethylbenzamide (400 mg) in DMF (2 ml) was added trichloroisocyanuric acid (120 mg) and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous sodium hydrogen carbonate-ethyl acetate. The organic layer was separated and washed with water, aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1–0:1) for purification to give the title compound (140 mg) as a colorless amorphous compound.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][S:7][CH:8]1[CH:16]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9]1.O.[OH-].[Li+]>C1COCC1.O>[C:18]1([CH2:17][CH:16]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][CH:8]2[S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCCSC1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCSC1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 50 mg (0.13 mmol) of 4-(3-naphthalen-1-ylmethyl-2,3-dihydro-imidazo[1,2-a]pyridin-2-ylsulfanyl)-butyric acid methyl ester in 2 mL of THF is treated with a solution of 11 mg (0.26 mmol) of lithium hydroxide monohydrate in 1 mL of water at room temperature. The resulting mixture is heated to 40° C., and stirred at this temperature for 3 h. Then the reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is diluted with water and neutralized with 1N HCl solution. The product is extracted with ethyl acetate, and the organic layer is separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 3˜10% methanol in dichloromethane solution to give the title compound. LCMS (ESMS): m/z 377 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:11][C:7]1[C:6]([F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[F:10]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1c(F)cc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A mixture of 4-nitro-2,6-difluoro-phenol (5.08 g, 29.0 mmol) and cesium carbonate (10.3 g, 31.7 mmol) in 100 mL acetonitrite was treated with methyl bromoacetate (3.0 mL, 31.7 mmol). The mixture was heated at reflux for 2 h. The mixture was allowed to cool to ambient temperature, and partitioned between water and ethyl acetate. The organic layer was separated and dried over sodium sulfate, filtered, and concentrated to afford material which was purified by silica gel chromatography eluting with hexane: ethyl acetate (2:1). Concentration of the relevant fractions afforded the title compound (6.11 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH2:12])([CH3:11])[CH2:6][CH2:5]2.[F:13][C:14]([F:25])([F:24])[C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH:12][C:21]([C:18]1([NH:17][C:15](=[O:16])[C:14]([F:13])([F:24])[F:25])[CH2:19][CH2:20]1)=[O:22])([CH3:11])[CH2:6][CH2:5]2
Reactant: CC1(N)CCc2cc(Br)ccc21
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Product: CC1(NC(=O)C2(NC(=O)C(F)(F)F)CC2)CCc2cc(Br)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], (rac)-5-bromo-1-methyl-indan-1-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to yield the title compound as light brown solid. MS: 402.9 (M−H−, 1Br).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=[C:8]2[C:13]=1[NH:12][CH2:11][CH2:10][NH:9]2)([O-:3])=[O:2].[CH:18](=O)[CH3:19]>>[CH2:18]([N:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=2)[NH:12][CH2:11][CH2:10]1)[CH3:19]
Reactant: COC(=O)c1cc2c(c([N+](=O)[O-])c1)NCCN2
Reactant: CC=O
Product: CCN1CCNc2c1cc(C(=O)OC)cc2[N+](=O)[O-]

Procedure:
Methyl 4-ethyl-8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D210) was prepared from methyl 8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D209) in an analogous manner to the process described for Ester 35 (B35) using acetaldehyde instead of propionaldehyde. [M+H]+=266.3, RT=3.07 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9]2)=[C:4]([CH3:19])[CH:3]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:3][C:4]=2[CH3:19])[CH2:10][CH2:9]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)ccc1C1(OCc2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1C1(OCc2ccccc2)CC1
Yield: 89.7 %

Procedure:
Using General Procedure D; 4-bromo-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 74, 320.0 mg, 1.00 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (19.0 mg, 0.1 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound (300.0 mg, 89%) was isolated by chromatography (0-2% EtOAc-hexanes).
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:33][C:34]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1)(=O)C1C=CC=CC=1.[ClH:44].CON.N1C=CC=CC=1>C1COCC1.CO.C(O)C>[ClH:44].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:33][C:34]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)nc1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(N)=N4)c2)nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-cyano-pyridine-2-carboxamide (133 mg, 0.22 mmol, isomer 1) is dissolved in THF (1 mL) and diluted with methanol (3 mL) and ethanol (3 mL). O-Methylhydroxylamine hydrochloride (190 mg, 2.2 mmol) and pyridine (180 μL, 2.2 mmol) are added. The reaction is warmed to 50° C. and stirred overnight. The mixture is concentrated onto silica gel (˜10 g) and purified via silica gel chromatography eluting with a 0-10% gradient of 7 N ammonia methanol in dichloromethane. The material is purified a second time on a SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol. The mixture is purified a final time over silica gel with a 0% to 10% gradient of 7 N ammonia methanol in dichloromethane to give the free base of the title compound. This material is dissolved in dichloromethane (5 mL) and 1 M hydrogen chloride in diethyl ether (0.27 mL, 270 μmol) is added. The solvent is removed in vacuo to give the title compound (114 mg, 97%). ES/MS (m/e): 493 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]>>[N+:1]([C:19]1[CH:20]=[CH:21][C:13]([O:12][C:11]([F:10])([F:23])[F:22])=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])([O-:4])=[O:2]
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1[N+](=O)[O-]

Procedure:
29.7 ml of nitric acid were added dropwise to 76.5 ml of concentrated sulfuric acid, while cooling and stirring, and 9.0 g (43.7 mmol) of 3-trifluoromethoxybenzoic acid were then added. The reaction mixture was heated at 50°-55° C. for 1 hour and, after cooling, was poured onto ice, and the residue was filtered off with suction to give, after drying, 8.8 g of product, melting point 90°-93° C. (sintering at 85° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][CH:10]([C:8]2[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1ccncc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccncc1
Temperature: 90 °C
Yield: 25.5 %

Procedure:
A mixture of 1-(6-fluoro-1-pyridin-4-yl-1H-benzoimidazol-2-yl)ethylamine (55 mg, 0.22 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (33 mg, 0.22 mmol) and DIPEA (115 μL, 0.64 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 296 as a pale beige solid (21 mg, 26%). LCMS (Method K): RT 3.00 min [M+H]+ 375.06. 1H NMR (DMSO-d6, 400 MHz): δ 8.75-8.71 (2H, m), 7.88 (1H, s), 7.79-7.72 (2H, m), 7.65-7.60 (2H, m), 7.24-7.12 (3H, m), 7.06 (1H, dd, J=8.98, 2.49 Hz), 5.65-7.56 (1H, m), 1.57 (3H, d, J=6.77 Hz)
Reaction SMILES: COC1C=CC(S([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][CH:16]=2)(=O)=O)=CC=1.O[C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][O:12][C:34]3[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=3)=[CH:16][CH:17]=2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)OCCc2ccc(OS(=O)(=O)c3ccc(OC)cc3)cc2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)Oc2ccc(CCOc3ccc(C=O)cc3)cc2)cc1
Yield: 101.4 %

Procedure:
A mixture of 8.5 g (17.8 mmole) 4-(4-methoxyphenylsulfonyloxy)phenethyl 4-methoxy-1-benzenesulfonate, 2.16 g (17.7 mmole) 4-hydroxybenzaldehyde and 10 g (72.5 mmole) potassium carbonate in 60 g acetonitrile was refluxed over night. The salt was filtered off and the solvent was evaporated. The crude product was purified on silica gel using dichloromethane as eluent to give 7.4 g of 4-[2-(4-formylphenoxy)ethyl]phenyl 4-methoxy-1-benzenesulfonate (slightly polluted with the corresponding styrene product).
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH:7]=[C:6]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH3:15])[CH2:5][CH:4]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:13]([N:12]1[C@@H:7]2[C@@H:6]([CH2:5][CH2:4][C:3](=[O:2])[CH2:8]2)[CH2:9][CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: CCCNCCCC1=CCC(OC)=CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCN1CCC[C@@H]2CCC(=O)C[C@@H]21
Yield: 22.7 %

Procedure:
One hundred twenty-one grams of 1-methoxy-4-(3-n-propylamino)propyl-1,4-cyclohexadiene were dissolved in 1 l of 15% aqueous sulfuric acid. The acidic solution was refluxed for about 6 hours and was then poured over ice. The dilute acidic solution was made basic with 50% aqueous sodium hydroxide. The now-basic aqueous solution was extracted with methylene dichloride. The methylene dichloride extract was dried and the solvent removed therefrom to yield 25.6 g of cis-(±)-1-n-propyl-7-oxodecahydroquinoline.