Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C@H:11]1[C@@H:18]2[N:14]([C:15](=[O:32])[N:16]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=3)[C:17]2=[O:19])[CH2:13][CH2:12]1>C(Cl)Cl>[F:7][CH:11]1[CH:18]2[N:14]([C:15](=[O:32])[N:16]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=3)[C:17]2=[O:19])[CH2:13][CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12
Solvent: ClCCl
Product: N#Cc1ccc(N2C(=O)C3C(F)CCN3C2=O)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of diethylaminosulfur trifluoride (0.073 mL, 0.45 mmol) in CH2Cl2 (2 mL) cooled at −78° C. in a flame-dried flask under argon was added dropwise a solution of 6C (92 mg, 0.3 mmol) in CH2Cl2 (12 mL). After addition, the reaction mixture was stirred at −78° C. for 30 min, then at 0° C. overnight. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The separated aqueous layer was extracted with CH2Cl2 (2×). The combined CH2Cl2 layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with EtOAc/hexane (1:2) to give 52 mg of the title compound (racemate) as a white solid. m.p. 228-230° C.; HPLC: 99% at 5.0 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 641 [2M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[OH:15])=[CH:5][CH:4]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:15][C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@:9]2([OH:16])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc([C@@]2(O)CCCC[C@@H]2O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@]2(O)CCCC[C@@H]2OS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
[1S*,2S*]-1-(4-methoxyphenyl)cyclohexane-1,2-diol (2.02 g, 9.1 mmole, prepared in Part A above) was dissolved in pyridine (25 mL) and cooled in ice bath, then p-toluenesulfonyl chloride (2.71 g, 14.3 mmole) was added in portions. The resultant orange solution was allowed to warm to ambient temperature over a period of about 1 hours, stirred at ambient temperature overnight, and then added slowly to ice-water with stirring. The resultant gray solids were filtered and dried to yield the desired crude product (1.073 g). Recrystallization from benzene/petroleum ether gave the purified product as pale straw-colored plates (0.88 g, 0.23 mmole, 25% yield based upon the diol starting material). Treatment of a saturated benzene solution of this purified product with charcoal and recrystallization by addition of petroleum ether to the benzene solution resulted in a product in the form of white plates.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](N3CCCCC3)[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1.Cl.C[OH:31]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][C:11](=[O:31])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1
Reactant: CO
Agent: Cl
Solvent: O
Product: CN1CCC(=C2c3ccccc3CC(=O)c3ccccc32)CC1

Procedure:
1-Methyl-4-(10-(1-piperidyl)-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.4 g., is refluxed for 4 hours with 100 ml. of 10% HCl in water and 50 ml. of methanol. The methanol is evaporated and the remaining oil and water is made basic with solid NaHCO3 until no more CO2 is evolved. It is then extracted three times with 50 ml. each of toluene, combined extracts dried over MgSO4, filtered, and the toluene evaporated on a rotary evaporator leaving a residual product which crystallizes on standing. Three recrystallizations of this product from hexane gives 1-methyl-4-(10,11-dihydro-10-oxo-dibenzo[a,d]cyclo-hepten-5-ylidene)piperidine, m.p. 142°-143°C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([CH3:10])=[O:9].O=S(Cl)Cl.[CH3:25][CH2:26]O>>[C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([NH2:1])[C:11]([O:13][CH2:25][CH3:26])=[O:12])(=[O:9])[CH3:10]
Reactant: CCO
Reactant: CC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](N)CCCCNC(C)=O
Temperature: -10 °C
Yield: 80 %

Procedure:
Boc-Lys(Ac)-OH (1 equivalent, 0.2 g, 0.69 mmol) was dissolved in EtOH (2 mL). The reaction mixture was cooled at −10° C., and SOCl2 (1.5 equivalent, 76 μl, 1.035 mmol) was added dropwise. The mixture was allowed to warm to room temperature, then heated at 40° C. for 20 h (TLC control). The reaction mixture was concentrated and the crude was purified by flash chromatography (CH2Cl2/MeOH) to afford the compound (120 mg, 80%) as a white solid Rf=0.62 (CH2Cl2/MeOH 70/30).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.C(N(CC)CC)C.O[CH2:30][CH2:31][C@H:32]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:33]1[N:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:37](=[O:45])[C:36]2=[CH:46][CH:47]=[CH:48][N:35]2[N:34]=1>ClCCl.O>[Br:20][CH2:30][CH2:31][C@H:32]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:33]1[N:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:37](=[O:45])[C:36]2=[CH:46][CH:47]=[CH:48][N:35]2[N:34]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCBr)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Triphenylphosphine (170 mg, 0.44 mmol) was dissolved in 2 mL anhydrous dichloromethane. Bromine (32 μl, 0.62 mmol) was added dropwise under argon atmosphere and the reaction was stirred at room temperature for 30 min. Triethylamine (247 μl, 1.77 mmol) and (S)-tert-butyl (3-hydroxy-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (170 mg, 0.44 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with dichlorometane. The organics were dried over sodium sulphate, filtered and evaporated. The residue purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to obtain 147 mg (74% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH3:69])[CH:64]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)([CH:45]2[CH2:46][CH2:47][N:48]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([CH3:69])[CH:64]=3)[CH2:49][CH2:50]2)[OH:44])=[CH:39][CH:38]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1cccc(OCCCCl)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)O
Solvent: CCCCO
Product: Cc1cccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1
Yield: 62 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [α,α-bis(4 -fluorophenyl)]-4-piperidinemethanol, 1.8 g (0.01 mole) of 1-chloro-3-(3-methylphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 2.8 g (62%) of the title compound as a white solid, mp 112.5°-114° C. (2-propanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH3:12])=[C:4]([CH3:21])[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CS(C)=O>[NH2:1][C:2]1[N:7]2[N:22]=[N:23][N:24]=[C:6]2[C:5]([CH2:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH3:12])=[C:4]([CH3:21])[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=CCc1c(C)nc(N)nc1Cl)c1cc(Cl)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=CCc1c(C)nc(N)n2nnnc12)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Yield: 85.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 2.0 grams (0.006 mole) of 2-amino-4-chloro-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine, 0.4 gram (0.006 mole) of sodium azide, and 0.3 gram (0.006 mole) of ammonium chloride in 15 mL of dimethyl sulfoxide is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is poured into ice-water. The mixture is stirred until the ice melted, and the resultant solid is collected by filtration. The solid is dissolved in methylene chloride, and the solution is dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to a residual solid. The solid is recrystallized from methylene chloride/petroleum ether, yielding 1.8 grams of 5-amino-7-methyl-8-[3-(2,5-dichlorophenyl)-2-butenyl]tetrazolo[1,5-c]-pyrimidine. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[C:4]([CH3:10])[CH:3]=1.[CH:11](=O)[CH2:12][CH3:13]>C(O)C.Cl.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH3:10])[CH:3]=1)[NH:8][CH:11]=[C:12]2[CH3:13]
Reactant: Cc1cc(Br)ccc1NN
Reactant: CCC=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1c[nH]c2c(C)cc(Br)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19.8 %

Procedure:
To a suspenstion of (4-bromo-2-methylphenyl)hydrazine (1.44 g, 7.16 mmol) in ethanol (10 mL) was added propionaldehyde (0.68 mL, 9.3 mmol). The solution became clear and the mixture was stirred at room temperature for 45 minutes. The solvents were removed and anhydrous ZnCl2 (1.07 g, 7.88 mmol) was added and the mixture was heated at 170° C. for 30 minutes. The mixture was cooled to room temperature, diluted with 10% HCl, extracted with CH2Cl2 and the organic extract was dried over MgSO4. After filtration and concentration, the residue was purified by CombiFlash (0-10% EtOAc/heptane) to provide 5-bromo-3,7-dimethyl-1H-indole (317 mg, 20%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[CH:16][C:15]=2[F:23])[CH:10]([CH2:25][CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC(OC(=O)C(C)=O)(C2C3OC=CC=3C=CC=2F)C(CC)C1)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[CH:16][C:15]=2[F:23])[C@H:10]([CH2:25][CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1CN(Cc2ccccc2)CCC1(O)c1c(F)ccc2ccoc12
Agent: CCC1CN(Cc2ccccc2)CCC1(OC(=O)C(C)=O)c1c(F)ccc2ccoc12
Product: CC[C@@H]1CN(Cc2ccccc2)CC[C@@H]1c1c(F)ccc2ccoc12
Yield: 95.1 %

Procedure:
Beginning with 5.4 gm (15.3 mMol) 1-benzyl-3-ethyl-4-hydroxy-4-(6-fluorobenzofur-7-yl)piperidine, 5.91 gm (88%) 1-benzyl-3-ethyl-4-(methyl oxoacetoxy)-4-(6-fluorobenzofur-7-yl)piperidine was recovered as an orange oil, essentially as described in EXAMPLE 16. This material was treated with tri(n-butyl)tin hydride essentially as described in EXAMPLE 16 to provide 4.91 gm of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C[Si](C)(C)[C:11]#[C:12][CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C>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.[Cu]I.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]#[C:12][CH3:13])[N:5]=[CH:4][N:3]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Clc1cc(Cl)ncn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC#Cc1cc(Cl)ncn1
Temperature: 60 °C
Reaction time: 9 h
Yield: 40.4 %

Procedure:
Under argon atmosphere, a mixture of 4,6-dichloropyrimidine (500 mg, 3.36 mmol), 1-(trimethylsilyl)-1-propyne (0.497 mL, 3.36 mmol), tetrabutylammonium fluoride (1 M in THF, 3.36 mL, 3.36 mmol), triethylamine (1.54 mL, 11.1 mmol), tetrakis(triphenylphosphine)palladium(0) (194 mg, 0.168 mmol), copper(I) iodide (192 mg, 1.01 mmol) and toluene (20 mL) was stirred for 9 hours at 60° C. The mixture was cooled down to ambient temperature, and water was added to the mixture. The mixture was extracted with CHCl3, and the organic layer was dried over MgSO4 and filtered. The filtrate was concentrated at reduced pressure, and purification of the residue with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 20%) afforded 4-chloro-6-(prop-1-yn-1-yl)pyrimidine (207 mg).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:14](=[O:15])[C:13]2[CH2:16][NH:17][CH2:18][CH2:19][C:12]=2[NH:11][C:10]1=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]=O.Cl>C(O)=O>[ClH:1].[CH2:2]([N:9]1[C:14](=[O:15])[C:13]2[CH2:16][N:17]([CH3:21])[CH2:18][CH2:19][C:12]=2[NH:11][C:10]1=[O:20])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CNCC2
Agent: Cl
Solvent: O=CO
Product: CN1CCc2[nH]c(=O)n(Cc3ccccc3)c(=O)c2C1

Procedure:
6.5 g of 3-benzy1-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]-pyrimidine-2,4-dione hydrochloride were added at 0° C. to a mixture of 5.5 ml of 90% formic acid and 4 ml of 37% formaldehyde, with stirring. After heating for 8 h at the reflux temperature, 26.5 ml of i N hydrochloric acid were added at room temperature and the mixture was then concentrated under reduced pressure. After recrystallization from isopropanol/water, 3-benzyl-6-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione hydrochloride was obtained from the residue.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[CH2:16][CH2:15][C:14]([O:18][C:19]3[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:12]=2[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[N:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CN(C=O)C>[CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:20]=[C:21]([NH:25][C:32]([C:30]4[S:31][C:27]([CH3:26])=[CH:28][N:29]=4)=[O:33])[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(OC2=Cc3[nH]nc(C=Cc4ccccc4)c3CC2)c1
Reactant: Cc1cnc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)Nc2cccc(Oc3ccc4c(C=Cc5ccccc5)n[nH]c4c3)c2)s1

Procedure:
3-(3-Styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine was converted to 5-methyl-thiazole-2-carboxylic acid {3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-1H-indazol-6-yloxyl-phenyl}amide by treatment with 5-methyl-thiazole-2-carboxylic acid and HATU (o-(2-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) in DMF and analogous work-up, DDQ treatment and isolation to Example 4(a), step (iv) (50% yield): 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 8.45 (d, 1H, J=9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H), 7.54-7.34 (m, 5H), 6.96 (d, 1H, J=8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH:14]C(OC(C)(C)C)=O)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(NC(=O)OC(C)(C)C)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccc(N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
The mixture of 2-ethanoyloxy-5-tert-butoxycarbonylaminobenzoic acid (1.01 g, 3.42 mmole) in TFA/CH2Cl2 (20.0 ml. 1:1 v/v) was stirred for 30 min at room temperature. After the reaction mixture was concentrated, the residue was dissolved in ether. The resulting residue was recrystallized from ethyl acetate/hexane to give 0.65 g (97% yield) of 2-ethanoyloxy-5-aminobenzoic acid as a white solid.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][C:17](=[O:22])[C:18](OC)=[O:19])[CH2:10][C:9]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C1(C)C=CC=CC=1>[CH:1]1([O:7][N:8]2[C:13]([CH3:14])([CH3:15])[CH2:12][CH:11]([NH:16][C:17]([C:18]([NH:28][CH2:27][CH2:25][OH:26])=[O:19])=[O:22])[CH2:10][C:9]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: COC(=O)C(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Solvent: Cc1ccccc1
Product: CC1(C)CC(NC(=O)C(=O)NCCO)CC(C)(C)N1OC1CCCCC1
Yield: 63.9 %

Procedure:
A mixture of 9.1 grams (26.7 mmol) of methyl N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)oxamate, 1.8 grams (29.4 mmol) of ethanolamine and 35 ml of toluene is heated at reflux for 30 minutes. Methanol is removed from the reaction mixture by fractional distillation. The reaction mixture is poured into ethyl acetate (125 ml) to afford 6.3 grams (64% yield) of the title compound as a white solid melting at 190°-192° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.[CH2:15](I)[CH3:16].O>CN(C=O)C>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:15][CH3:16])[CH:10]=2)[CH:5]=1
Reactant: CCI
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2cc(Br)ccc2c1
Yield: 60 %

Procedure:
To a suspension of sodium hydride (800 mg, 60% oil dispersion) in DMF (20 ml) was added a solution of 6-Bromo-2-naphthol dropwise with stirring at 0°. After gas evolution had ceased, neat ethyl iodide (1.6 ml) was added dropwise to the stirred solution. The reaction was stirred overnight at rt. The reaction mixture was poured into water and extracted several times with tert-butyl methyl ether. The combined organic extracts were washed with water and brine, then dried over MgSO4, filtered and evaporated under reduced pressure to give tan solid. This was recrystallized from MeOH and dried under high vacuum to a constant wt. giving a white solid (3.11 g, 60%). 1H NMR(400 MHz, CDCl3) δ 7.92 (d, J=1.7 Hz, 1H), 7.65(d, J=8.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.16 (dd, J=8.9 Hz, 2.48, 1H), 7.09 (d, J=2.4 Hz, 1H), 4.15 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)([OH:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].O.[CH2:40](O)[CH3:41]>>[CH2:40]([O:2][C:1]([CH2:4][CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][S:20]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)(=[O:21])=[O:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3])[CH3:41]
Reactant: O=C(O)CCn1c2c(c3ccccc31)C[C@H](NS(=O)(=O)c1ccncc1)CC2
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCn1c2c(c3ccccc31)C[C@H](NS(=O)(=O)c1ccncc1)CC2
Temperature: 25 °C

Procedure:
0.9 g (2.3 mmol) of 9-(2-carboxyethyl)-3(R)-(4-pyridylsulphonamido)-1,2,3,4-tetrahydrocarbazole is dissolved in 50 ml of ethanol p.a., 3 ml of concentrated sulphuric acid are added and the mixture is boiled under reflux for 1.5 hours with stirring. After cooling to room temperature, 12.0 g of sodium hydrogen carbonate are added, water is added after the evolution of gas has ended and the mixture is extracted several times with ethyl acetate. The combined organic phases are dried with sodium sulphate and the solvent evaporated therefrom. The crude product is purified by chromatography on silica gel 60 (40-63 μm, Merck, eluant: CH2Cl2 :CH3OH=10:1). Rf =0.63 (CH2Cl2 :CH3OH=10:1)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][C:6]1=[O:13])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2([OH:13])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH2:10][CH:5]2[CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])=[CH:20][CH:19]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCOC(OCC)C1CC(C)(C)CCC1=O
Product: CCOC(OCC)C1CC(C)(C)CCC1(O)c1ccc(Cl)cc1

Procedure:
reacting the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol and isolating or not isolating the 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol; and
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=1.N1C(C)=CC=CC=1C>ClCCl.CN(C)C=O.C(#N)C>[NH2:32][C:26]1[N:27]=[C:28]([NH:31][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[O:9])[CH:29]=[CH:30][C:25]=1[C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[Cl:16]
Reactant: COc1ccc(Cl)c(-c2ccc(N)nc2N)c1
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1ccc(Cl)c(-c2ccc(NC(=O)c3ccnn3C)nc2N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (5.28 g, 41.9 mmol) in dichloromethane (55 ml) was added oxalyl chloride (9.14 ml, 104.8 mmol) followed by 3 drops of dimethylformamide. The reaction was stirred at room temperature for 18 hours before concentration in vacuo. The residue was dissolved in acetonitrile (42 ml) and added dropwise to a cooled solution of 3-(2-chloro-5-methoxyphenyl)pyridine-2,6-diamine (preparation 1, 9.5 g, 38 mmol) and lutidine (6.6 ml, 57.1 mmol) in acetonitrile (650 ml). The reaction was allowed to warm to room temperature and stirred under nitrogen for 2 hours. The reaction was quenched by the addition of water (300 ml) and concentrated to low volume in vacuo. The aqueous residue was washed with dichloromethane (2×300 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethylacetate:heptane 1:4 to furnish a solid. This was recrystallised from toluene (100 ml) to afford 6.7 g of the title product.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cncc(Br)c1
Product: CS(=O)(=O)c1cncc(C#Cc2cc(Cl)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 5-bromo-3-methylsulfonylpyridine (Combiblocks), the title compound was obtained as a white solid after purification by flash column chromatography (silica).