Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:21])[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:21])[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)C(=O)Nc3ccccc3C2=O)cc1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(O)cc2)C(=O)Nc2ccccc2C1=O
Yield: 49.5 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(4-methoxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (1.00 g, 3.55 mmol) and BBr3 (17.8 mL, 1.0 M solution in dichloromethane). After normal workup, the pure objective compound (0.47 g, 50%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.81 (s, 3H, CH3), 5.20 (br s, 1H, OH), 6.68 (d, J=8.9 Hz, 2H, ArH), 6.85-7.19 (m, 4H, ArH), 7.45-7.89 (m, 2H, ArH), 8.46 (br s, 1H, NH).
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH2:5][CH2:6][CH2:7][N:8]=1.CC(C)([O-])C.[K+].[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][NH:35][C:36](=[O:49])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45](OC)=[O:46])=[CH:39][CH:38]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>CN(C)C=O>[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][NH:35][C:36](=[O:49])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45](=[O:46])[NH:2][C:3]2[NH:8][CH2:7][CH2:6][CH2:5][N:4]=2)=[CH:39][CH:38]=1)[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.25 g (9.2 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride and 1.03 g (9.2 mmol) of potassium tert-butoxide were dissolved in 3 ml of absolute dimethylformamide and the mixture was stirred at room temperature for 30 min. 740 mg (1.53 mmol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionate (step c) in 1 ml of dimethylformamide were then added and the mixture was stirred at room temperature for 4 h. It was then adjusted to pH 4 using glacial acetic acid, the solvent was stripped off in vacuo, and the residue was chromatographed on silica gel (dichloromethane/methanol/glacial acetic acid/water (9/1/0.1/0.1)). Yield: 190 mg (38%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH2:15][C:14](=[O:16])[N:13]3[C:9](=[N:10][C:11]4[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=43)[CH2:8]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(C2CC(=O)N3C(=[N:37]C4C=CC(I)=CC=43)C2)=CC=1.N>O1CCOCC1.O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:8][C:9]2[NH:10][C:11]3[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:15][C:14]([NH2:37])=[O:16])=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3ccc(I)cc3n21
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3cc(I)ccc3n21
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(-c2ccccc2)cc1

Procedure:
The 1:1-mixture of 3-(biphenyl-4-yl)-7-iodo-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 3-(biphenyl-4-yl)-8-iodo-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (140 mg) was dissolved in 1,4-dioxane (2 ml) at reflux temperature. A 25% solution of ammonia in water (1 ml) was added and refluxing was continued for 2 h while addition of 25% ammonia solution in 1 ml portions was repeated every half an hour (3 times). Then all volatiles were removed at the water aspirator and the residue was triturated with acetone to leave 3-(biphenyl-4-yl)-4-(5-iodo-2-benzimidazolyl)-butyramide (85 mg) as light colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][O:19][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Yield: 98.7 %

Procedure:
Into a 200 cc glass reactor equipped with a stirrer, 26.3 g of ethyl 2-chloro-4,5-difluorobenzoylacetate, 23.7 g of ethyl ortho-formate and-. 40 ml of acetic anhydride were charged, and reacted at a reaction temperature of from 120° to 135° C. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure to obtain 31.5 g of the desired compound as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.O.NN>C(O)C.Cl[Fe](Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccncc2F)cc1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccncc2F)cc1
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a refluxing mixture of 3-fluoro-4-(4-nitrophenyl)pyridine (2.23 g), trichloroiron (130 mg) and activated carbon (1.12 g, 50 wt % of the starting material) in ethanol (74 mL) was added dropwise hydrazine hydrate (1.6 g), and the mixture was stirred for 3 hours. The insoluble materials were removed by filtration in hot and washed with ethanol. Most of ethanol was removed in vacuo, and to the residue was added water. Resulting solid was collected by filtration, and purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:2) to afford 4-(3-fluoropyridin-4-yl)aniline (1.36 g) a pale orange solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[H-].[Na+].O>CN(C)C=O>[CH2:7]([N:6]1[C:2]([O:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[C:4]([CH3:9])=[N:5]1)[CH3:8]
Reactant: COc1ccc(O)cc1
Reactant: CCn1nc(C)c(C(=O)c2ccccc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C)c(C(=O)c2ccccc2)c1Oc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 57.3 %

Procedure:
A mixture of 129 mg of (5-chloro-1-ethyl-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone, 141 mg of 4-methoxyphenol and 33 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 110° C. for 5 h. Water (8 ml) was added and the mixture was extracted three times with 10 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:3) for the elution to give 100 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone as a yellow oil. Mass spectrum (ES) m/z 337 [M]+, 378 [M+H+CH3CN]+.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]2[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)=[O:16]
Reactant: Nc1ccccn1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccccn3)ccc12
Yield: 28.7 %

Procedure:
This compound was prepared according to the method of Example 15, using 49 mg (0.177 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 18 mg (0.195 mmol, 1.1 equiv) 2-aminopyridine as starting materials, to give 17 mg (34%) of yellow amorphous foam: HRMS calcd for C20H22N4O+H: 335:1872. Found: 335.1874.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]1[C:16]([O:18]CC)=O.[C:21]1([CH2:27][C:28]([NH2:30])=[NH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[O-].[Na+]>CO>[CH2:27]([C:28]1[NH:30][C:16](=[O:18])[C:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8][C:2]=2[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)[nH]c(=O)c2CC1
Reaction time: 8 h
Yield: 83.1 %

Procedure:
1-Tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (See WO2006029154, example 1a, p 34) (1.32 g, 4.6 mmol) and 2-phenyl-acetamidine (750 mg, 4.4 mmol) were added to a solution of NaOMe (3.8M, 3.5 mL, 13.2 mmol) in MeOH (15.0 mL) at 0° C. and stirred at 0° C. to room temperature overnight. The reaction was quenched with water, partitioned with ethyl acetate and the phases separated. The combined organics layer were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the crude product as an orange gum. The residue was purified by flash column chromatography eluting with CH2Cl2:ethyl acetate (90:10 to 70:30) to afford the title compound as a white solid (1.30 g, 83% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[C:22]([NH:25][CH2:26][CH:27]1[CH:31]([Cl:32])[CH2:30][NH:29][CH2:28]1)(=[O:24])[CH3:23]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:29]1[CH2:30][CH:31]([Cl:32])[CH:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH2:28]1)[N:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: CC(=O)NCC1CNCC1Cl
Reactant: O=C(O)c1cn(-c2cccs2)c2cc(F)c(F)cc2c1=O
Solvent: CN1CCCC1=O
Product: CC(=O)NCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2cccs2)CC1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
6,7-Difluoro-1-(2-thienyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.5 g) and 3-acetylaminomethyl-4-chloropyrrolidine (0.86 g) are added to N-methylpyrrolidone (50 ml) and the mixture is stirred at 110° C. for one hour. After the reaction, the solvent is distilled off and the resulting residue is crystallized with ethanol. The crystals are separated by filtration and then recrystallized from ethanol to give 6-fluoro-1-(2-thienyl)7-(3-acetylaminomethyl-4-chloro-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.54 g) powder, m.p. 145° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19]>>[CH3:15][C:16]1[CH:17]=[C:18]([NH:19][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Cc1ccc(N)cc1C
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C)c(C)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3,4-dimethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C@H:12]2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=O)=[CH:6][CH:5]=1.[ClH:31]>C(#N)C.O=P(Cl)(Cl)Cl>[ClH:31].[CH3:25][O:24][C:21]1[C:20]([O:26][CH3:27])=[CH:19][C:18]2[C@H:12]3[C@H:11]([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]3)[N:10]=[C:8]([C:7]3[CH:28]=[CH:29][C:4]([C:3]([O:2][CH3:1])=[O:30])=[CH:5][CH:6]=3)[C:23]=2[CH:22]=1
Reactant: COC(=O)c1ccc(C(=O)N[C@H]2CCN(C)C[C@H]2c2ccc(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C2=N[C@H]3CCN(C)C[C@H]3c3cc(OC)c(OC)cc32)cc1

Procedure:
2.31 g of (-)-cis-terephthalic acid N-[3-(3,4-dimethoxyphenyl)-1-methylpiperidin-4-yl]amide mono-methyl ester are heated to boiling under reflux for 4 h in 25 ml of acetonitrile and 3 ml of phosphorus oxytrichloride. After distilling off the excess phosphorus oxytrichloride, the residue is partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The solid residue is purified by silica gel chromatography, the main product fraction is separated and this is concentrated. The solid residue is dissolved in a little methanol, and the solution is treated with one equivalent of aqueous HCl and concentrated. The solid residue is recrystallized in methanol/diethyl ether. 1.76 g (70% of theory) of the title compound are obtained as a 1.25-hydrochloride 0.5-hydrate having the m.p. 188-192° C. (unsharp, slow deliquescence).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: Clc1ncccn1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1ncccn1)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=550.1 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloropyrimidine.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][C:6]([F:12])([F:11])[C:7]([O:9]C)=[O:8].CCOCC>O>[Br:2][CH2:3][CH2:4][CH2:5][C:6]([F:12])([F:11])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(F)(F)CCCBr
Agent: Br
Solvent: O
Solvent: CCOCC
Product: O=C(O)C(F)(F)CCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HBr gas was introduced into 48% HBr in H2O (100 ml) with occasional cooling in an ice bath until the weight became 180 g. The HBr solution was then added to Part (5) compound (8.4 g, 36.3 mmole) at room temperature and the reaction was stirred for 5 hours at room temperature. The reaction was cooled to 0° C. and poured into Et2O (900 ml) in an ice bath. The products were extracted into the Et2O layer. The water layer was further extracted with Et2O (200 ml and 100 ml). The combined ether layers were washed with H2O (200 ml). The H2O wash was backwashed with Et2O (100 ml). The Et2O layers were combined and dried over MgSO4. Filtration and evaporation of solvent gave the title compound (7.8 g, quant.) as a colorless liquid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)(=O)/C=C/C(O)=O.[CH3:17][N:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]([NH2:28])[CH2:20][CH2:19]1.[OH-].[Na+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)/C=C/C(O)=O>C(#N)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:17][N:18]1[C:22]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:21]([NH:28][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(N)C12CCCCC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CN1CCC(NC(=O)c2ccccc2)C12CCCCC2
Reaction time: 24 h
Yield: 25.7 %

Procedure:
To a stirring suspension of 3.5 g (0.021 mole) of 1-methyl-4-amino-1-azaspiro[4.5]decane of Example 2 and 150 ml of 10% NaOH was added dropwise 3.1 g (0.022 mole) of benzoyl chloride. The reaction was stirred vigorously for 24 hours, the aqueous solution was decanted and the remaining oil was dissolved in ethyl acetate and dried over Na2SO4. The solvent was then evaporated to give a solid which was recrystallized from hexane to give 2.5 g. The solid was dissolved in 10 ml of acetonitrile and 1.1 g of fumaric acid was added. The suspension was stirred until the amine salt precipitated from solution. The compound was filtered and recrystallized twice from ethanol-ether to give 2.1 g (25.7%) of 1-methyl-4-benzamido-1-azaspiro[4.5]decane fumarate, m.p. 171°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH3:11])[CH:3]=1.Br[C:13]1C=CC(C=C)=C(CC)C=1.B1C2CCCC1CCC2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH2:11][CH3:13])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1CC
Reactant: Cc1cc(Br)ccc1CCO
Agent: B1C2CCCC1CCC2
Product: CCc1cc(Br)ccc1CCO
Yield: 81 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 36A (1.98 g, 5.1 mmol) was heated in a pressure vessel with 9-BBN at 100° C. for 15 h to yield 36B (0.95 g, 81%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.58 Hz, 3 H) 2.66 (q, J=7.58 Hz, 2 H) 2.87 (t, J=6.82 Hz, 2 H) 3.83 (t, J=6.82 Hz, 2 H) 7.06 (d, J=8.08 Hz, 1 H) 7.25-7.31 (m, 1 H) 7.32-7.37 (m, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])=[N:2]1.[H-].[Na+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C>[CH:20]1([CH2:23][N:1]2[CH:5]=[CH:4][C:3]([CH2:6][N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])=[N:2]2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccn(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a colorless solution of 2-(1H-pyrazol-3-ylmethyl)-1H-Isoindole-1,3(2H)-dione (CAN 95533-75-8; 3.66 g, 16.1 mmol) in DMF (80 mL) at 0° C. was added in 4 portions sodium hydride (1.29 g, 32.2 mmol) within 15 min. After warming to room temperature the mixture was stirred for 30 min and cyclopropylmethyl bromide (21.7 g, 15.6 mL, 161 mmol) in DMF (20 mL) was added within 30 min. The mixture was stirred for 22 h at room temperature, poured into ethyl acetate (200 mL) and extracted with water (3×100 mL). Water phases were washed with ethyl acetate (200 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 100% EtOAc in heptane) and finally by preparative HPLC to give 1.63 g (36%) of the title compound as a white solid; MS (EI): 282.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[CH:4]=1.[CH3:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15].O>CN(C=O)C>[Br:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:12]([CH3:11])(=[O:16])[O:13][CH2:14][CH3:15]
Reactant: BrCc1cccc(CBr)c1
Reactant: CCOP(C)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(C)(=O)Cc1cccc(CBr)c1
Temperature: 150 °C
Yield: 44 %

Procedure:
To a solution of α,α′-Bisbromo-m-xylene (7.75 g, 29.38 mmol) in DMF (10 mL) was added diethyl methylphosphonite (2.0 g, 14.69 mmol) via syringe. The mixture was heated to 150° C. for 2 minutes in a microwave. The reaction mixture was poured into water and product extracted with ethyl acetate (3×25 mL). The combined organics were washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. Reduced volume in vacuo and purified product by flash column eluting 20-100% ethyl acetate in hexanes to give 1.89 g mg (44%) 65 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.24 (t, 3H), 1.33 (d, 3H), 3.08 (d, 2H), 3.97 (dt, 2H), 4.44 (s, 2H), 7.25 (m, 4H). LCMS: m/z for C11H16BrO2P++H observed 291.0 and 293.0 at 2.09 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])=[CH:5][CH:4]=1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20].O>C1(C)C=CC=CC=1>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][C:9](=[CH:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:20]
Reactant: COc1ccc(C(=O)CS(=O)(=O)C(F)(F)F)cc1
Reactant: CCOC(CN)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(CNC(=CS(=O)(=O)C(F)(F)F)c1ccc(OC)cc1)OCC

Procedure:
A solution of 4'-methoxy-2-[(trifluoromethyl)sulfonyl]acetophenone (6.0 g, 0.021 mol) in toluene is treated with aminoacetaldehyde diethyl acetal (2.8 g, 0.021 mol), heated at reflux overnight with removal of water, and concentrated in vacuo to obtain the title product as an oil. This oil is used in Example 4 without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](Cl)(=[O:13])[CH3:12]>C(Cl)Cl>[C:11]([O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:13])[CH3:12]
Reactant: Cc1ccc(C=O)c(O)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)ccc1C=O
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a 0-5° C. solution of 2-hydroxy-4-methylbenzaldehyde (15 g, 110 mmol) in 250 mL of DCM was added TEA (30.7 ml, 220 mmol) followed by dropwise addition of acetyl chloride (8.65 g, 110 mmol) over 15 min. The reaction was stirred at 0-5° C. for 30 min. The reaction mixture was concentrated under reduced pressure. To this residue 100 mL of 1N HCl was added. The crude mixture was extracted with EtOAc×2. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow oil, 2-formyl-5-methylphenyl acetate (18 g). 1H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 3H), 2.40 (s, 3H), 7.13 (s, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 10.01 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([C@H:13]1[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)-3-(methylsulfonyloxy)piperidine-1-carboxylate (6.0 g, 14 mmol) in dimethyl sulfoxide (40 mL) was added sodium azide (9.11 g, 140 mmol), and the reaction mixture was stirred at 90° C. overnight under N2. The solution mixture was cooled to ˜30° C., diluted with ethyl acetate (˜300 mL), and washed with water (700 mL×3) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to the title compound (3.8 g, 72%) as a yellow oil. MS (ES+) C18H25N5O4 requires: 375, found: 276 [M+H−100]+, 373 [M+Na]+.