Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:13][N:14](C)[CH2:15][CH2:16][CH2:17]N=C=NCC.[CH2:24]([O:26][C:27](=[O:53])[C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([N:38]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]=1[F:37])[C:31](O)=[O:32])[CH3:25].CNCCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:24]([O:26][C:27](=[O:53])[C:28]1[C:36]([F:37])=[C:35]([N:38]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:34]=[C:30]([C:31]([N:14]([CH3:13])[CH2:15][CH2:16][CH3:17])=[O:32])[CH:29]=1)[CH3:25]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reactant: CCN=C=NCCCN(C)C
Agent: CCCNC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)c(F)c(N(Cc2ccccc2)Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Dissolve the 1-hydroxybenzotriazole hydrate (139 mg, 1.03 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (197 mg, 1.03 mmol) and 5-dibenzylamino-4-fluoro-isophthalic acid 3-ethyl ester (381 mg, 0.934 mmol) in dichloromethane (10.0 mL). Stir for 30 min. Add methylpropyl amine (68.3 mg, 0.93 mmol) to the reaction mixture. Stir the reaction for 4 h. Add 10% aqueous potassium carbonate solution (10 mL). Extract with dichloromethane (2×50 mL). Combine the organic layers, wash with water (20 mL), saturated aqueous sodium chloride (20 mL), dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 40:60 ethyl acetate:hexanes) to give the title compound (279 mg, 65%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].O>C1COCC1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[O:14])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Saturated aqueous potassium carbonate (190 mL) and 4-methoxybenzoyl chloride (60.8 g, 358 mmol) were added to a solution of glycine methyl ester (30.0 g, 239 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred for 3 h at 0° C. and then poured into water (100 mL). The resulting mixture was extracted with EtOAc (200 ml×2). The combined extracts were dried over anhydrous sodium sulfate and concentrated to afford methyl 2-(4-methoxybenzamido)acetate (46.2 g, 86% yield) as a colorless solid, which was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: NC(=O)c1cccc2oc(-c3cccc(N)c3)nc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nc3c(C(N)=O)cccc3o2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
To a solution of 2-(3-aminophenyl)benzo[d]oxazole-4-carboxamide (100 mg, 0.39 mmol) in dichloromethane (5 mL) was added pyridine (34 mg, 0.43 mmol), then acetyl chloride (32 mg, 0.41 mmol) was added at 0° C. stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure and re-crystallized in methanol to obtain a white solid of 2-(3-acetamidophenyl)benzo[d]oxazole-4-carboxamide (45 mg, yield 38%). 1H-NMR (400 MHz, DMSO-d6) δ 2.09 (s, 3H), 7.53-7.58 (m, 2H), 7.84-7.86 (d, J=8 Hz, 1H), 7.97-8.07 (m, 4H), 8.44 (s, 1H), 8.57 (s, 1H), 10.29 (s, 1H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:38]([C:34]3[S:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)c3cccs3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, thiophene-2-carbonyl chloride (29 mg, 197 mmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (9.6 mg, 28% of theory).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
A solution of diisopropylamine (4.86 mL, 34.70 mmol) in dry tetrahydrofuran (212.3 mL) was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (13.88 mL, 34.70 mmol). The resulting reaction mixture was stirred at −78° C for 15 min and then slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 31.55 mmol) in dry tetrahydrofuran (23.6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (9.43 mL). The resulting bright yellow solution was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (7.95 g, 37.86 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7.08 mL) was slowly added. The reaction mixture was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (5.74 g, 58.1%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[C:15]([CH3:28])=[C:16]([CH2:20][NH:21][S@@](C(C)(C)C)=O)[CH:17]=[N:18][CH:19]=1.[ClH:29]>CO>[ClH:29].[NH2:21][CH2:20][C:16]1[C:15]([CH3:28])=[C:14]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[N:9]([CH3:12])[C:8](=[O:13])[CH2:7][CH2:6]3)[CH:19]=[N:18][CH:17]=1
Reactant: Cc1c(CN[S@](=O)C(C)(C)C)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2
Agent: Cl
Solvent: CO
Product: Cc1c(CN)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2

Procedure:
In analogy to the procedure described for the preparation of example 42, reaction of (R)-2-methyl-propane-2-sulfinic acid [5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-4-methyl-pyridin-3-ylmethyl]-amide (example 225) with hydrogen chloride (in dixoane) in methanol gave the title compound as a light brown solid. MS: 300.5 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([C:11]1[C:12](=[O:29])[N:13]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH2:26][O:27][CH3:28])[CH:14]=[CH:15][CH:16]=1)C(OCC)=O)C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:28][O:27][CH2:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:5][C:4]([OH:30])=[O:3])[C:12]1=[O:29]
Reactant: CCOC(=O)C(C(=O)OCC)c1cccn(-c2ccc([N+](=O)[O-])cc2COC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
115 g (maximum 147 mmol) of the crude product of diethyl-{1-[2-(methoxymethyl)-4-nitrophenyl]-2-oxo-1,2-dihydropyridin-3-yl}malonate were introduced as initial charge in 470 ml of dioxane at RT, 940 ml of 2N sodium hydroxide solution were added and the reaction mixture was stirred for 1.5 h at RT. By adding 313 ml of concentrated hydrochloric acid, the pH was adjusted to 1 and the mixture was then stirred for 2 h at 50° C. After cooling to RT, extraction was carried out three times with in each case 1.17 l of ethyl acetate. The combined organic phases, were washed three times with in each case 780 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The residue was dissolved in a small amount of dichloromethane and chromatographically purified over 1.96 kg of silica gel (0.04-0.06 mm) with methanol:dichloromethane 5:95 to 1:9. The product fractions were evaporated to dryness on a rotary evaporator. 34.9 g (75% over 2 stages) of the desired product were isolated as oil.
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[C:3]([F:16])([F:15])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].[Cl:18][S:19](O)(=[O:21])=[O:20]>>[Cl:17][CH:2]([Cl:1])[C:3]([F:15])([F:16])[O:4][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][C:8]([S:19]([Cl:18])(=[O:21])=[O:20])=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1ccc([N+](=O)[O-])c(OC(F)(F)C(Cl)Cl)c1
Reactant: O=S(=O)(O)Cl
Product: Cc1cc(OC(F)(F)C(Cl)Cl)c([N+](=O)[O-])cc1S(=O)(=O)Cl

Procedure:
In a 500 ml stirred reaction flask equipped with thermometer, air condenser, dropping funnel and ice water bath was placed 50 ml of chlorosulfonic acid, and, while stirring at 0° to 10° C, there was added dropwise over a one-half hour period 17.2 g of 2-(2,2-dichloro-1,1-difluoroethoxy)-4-methyl-1-nitrobenzene. After stirring for 50 hours, the reaction mixture was poured over crushed ice. The organic phase was extracted with methylene chloride, and the extract was washed with dilute bicarbonate, decolorized with charcoal and dried. Evaporation of the solvent affored 10 g of 4-(2,2-dichloro-1,1-difluoroethoxy)-2-methyl-5-nitrobenzenesulfonyl chloride as a solid melting at 60°-61° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(O)CCC.C(OC(=O)C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Cl)nc(Cl)nc32)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 90 °C
Yield: 39.7 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.36 g, 1 mmol) in n-butyl alcohol (3 mL) was added 6-aminoindazole (0.27 g, 2 mmol) and DIPEA (0.27 mL, 1.5 mmol) at room temperature. After heating at 90° C. for 4 h, the mixture was diluted with ethylacetate and the organic layer was sequentially washed with 1N HCl, saturated NaHCO3, and brine. The organic extract was then dried over Na2SO4 and concentrated to give a crude residue, which was purified by flash column (Hex/EtOAc=1:1) to give 2-Chloro-N-(1H-indazol-6-yl)-5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.18 g).
Reaction SMILES: C[O-].[Na+].[C:4]1(C)[CH:9]=CC=C[CH:5]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(Cl)C=C>O>[CH2:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[CH:4]=[CH2:5]
Reactant: O=C1CCCN1
Reactant: Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C=CCCl
Solvent: O
Product: C=CCN1CCCC1=O
Yield: 89.9 %

Procedure:
To a 5 liter volume flask of glass equipped with a stirrer, a fractional distillation column, a thermometer and a dropping funnel, there were added 270.1 g (5.0 mol) of sodium methoxide and 2 liters of toluene. After 425.6 g (5.0 mol) of 2-pyrrolidone was dropwise added to the flask through the dropping funnel at room temperature, the resulting methanol was completely removed by the fractional distillation column. 6.9 g (25 mmol) of (Butyl-)4NCl was added as a phase transfer catalyst and 382.7 g (5.0 mol) of allyl chloride was dropwise added to the reaction mixture at a temperature ranging from 60° to 70° C. through the dropping funnel to react them. After the completion of the reaction, water was added to dissolve salts formed during the reaction and then the organic phase was removed. Then the organic phase was distilled to separate the fractions having a boiling point ranging from 75° to 76° C./4 mmHg. Thus, 562.5 g of 1-allyl-2-oxopyrrolidine was obtained in a yield of 89.9%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.O>C1(C)C=CC=CC=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:30]3[CH2:32][CH2:31]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3CC3)cc2)CC1

Procedure:
To a solution of 1-Boc-4-(4-bromophenoxy)piperidine (5 g) in toluene (70 mL) were added dichlorobis(tricyclohexylphosphine)palladium (II) (725 mg), tripotassium phosphate (14.9 g) and cyclopropylboronic acid (1.81 g), and the mixture was refluxed for 7 hr. After cooling, water was added, insoluble materials were filtered off, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated and the residue was purified by column chromatography to give 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester. 4-(4-Cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester was dissolve in ethyl acetate (3 mL), 4N hydrogen chloride/ethyl acetate (7 mL) was added, and the mixture was stirred at room temperature overnight. Water was added, and the mixture was washed with ethyl acetate. To the aqueous solution was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(4-cyclopropylphenoxy)piperidine (2.49 g). By reaction and treatment in the same manner as in Preparation Example 60 and using 6-bromonicotinic acid (1.2 g) and 4-(4-cyclopropylphenoxy)piperidine (1.4 g), the title compound (2.4 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[C:25](O)=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:25]([C@@H:23]3[CH2:24][C@H:22]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:26])[CH2:12][CH2:11]2)=[N:4][CH:3]=1
Reactant: Cc1cnc(NCC2CCNCC2)nc1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1

Procedure:
A solution of 5-methyl-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (5.00 g, 0.024 mol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (T. Riley et al., J. Med. Chem., (1972), 15, 1187) (3.93 g, 0.024 mol), EDC (6.97 g, 0.036 mol) and HOBt (4.91 g, 0.036 mol) in DMF (50 mL) was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate (400 mL), washed with aqueous saturated NaHCO3 (100 mL), water (5×100 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel 60 (400 g), eluting with 50–100% ethyl acetate in hexane to give 5-methyl-2-{[(1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methyl]amino}pyrimidine. M.S. (M+1): 351.
Reaction SMILES: [CH3:1][C:2]1([CH2:18][NH:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[N+:28]([O-])=O)[C:23]#[N:24])[CH2:17][CH2:16][CH2:15][C:4]2([O:8][C:7](=[O:9])[N:6]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5]2)[CH2:3]1.[C:31](OC)(OC)(OC)[CH2:32][CH3:33].C(O)(=O)CC.C(O)(C(F)(F)F)=O>C(O)CC.CC#N.[Fe]>[CH2:32]([C:33]1[N:19]([CH2:18][C:2]2([CH3:1])[CH2:17][CH2:16][CH2:15][C:4]3([O:8][C:7](=[O:9])[N:6]([CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:5]3)[CH2:3]2)[C:20]2[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:27]=2[N:28]=1)[CH3:31]
Reactant: CCC(OC)(OC)OC
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CNc3cc(C#N)ccc3[N+](=O)[O-])C2)OC1=O
Agent: [Fe]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Product: CCc1nc2ccc(C#N)cc2n1CC1(C)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Temperature: 65 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To an orange solution containing 3-(((7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (0.100 g, 0.241 mmol) in 1-propanol (2.41 mL) was added iron (325 mesh) (0.135 g, 2.41 mmol), trimethyl orthopropionate (0.324 g, 2.41 mmol), and propionic acid (0.179 g, 2.41 mmol). The reaction mixture was stirred at 65° C. for 2 h and then cooled to rt. The reaction was diluted with MeCN (2 mL) and filtered through an Acrodisc CR 25 mm syringe filter with a 0.2 μm PTFE membrane. The filtered solution was purified by reverse-phase HPLC (Sunfire Prep C18 (30×150 mm); Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA; gradient: 25-55% solvent A over 15 min; 25 mL/min elution; 220 nm detection) to afford the title compound (0.092 g, 69% yield) as the TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.07 (br. s., 1H), 7.83 (s, 1H), 7.69-7.79 (m, 1H), 4.08 (s, 2H), 3.32 (dd, J=8.78, 35.39 Hz, 2H), 3.01 (dd, J=14.05, 43.42 Hz, 2H), 2.05 (d, J=13.55 Hz, 1H), 1.85-1.99 (m, J=12.55 Hz, 2H), 1.48-1.77 (m, 5H), 1.20-1.44 (m, 8H), 0.96 (s, 9H). MS (m/z) 423.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(OC)OC)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(OC)c1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-chloro-4-methanesulfonyl-3-dimethoxymethylbenzoate in an amount of 3.0 g (9.3 mmol) was dissolved in methanol in a volume of 30 ml, and to the resulting solution, was added 10% aqueous solution of sodium hydroxide in a volume of 20 ml, and then, the mixture was stirred for 1 hour at an ambient temperature. The reacted-mixture was then added with 1-N hydrochloric acid to make it acidic, and crystals precipitated were filtrated, washed with water and dried to obtain the objective compound in an amount of 2.5 g.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[O:28])[CH3:27])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH3:29][Mg]Br>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])([CH3:29])[CH3:27])(=[O:18])=[O:19])=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: CC(=O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Reaction time: 1.25 h
Yield: 78.6 %

Procedure:
A stirred THF (1 mL) solution of 1-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanone (Example 141; 65 mg, 0.17 mmol) was treated with methyl magnesium bromide (3 N in Et2O; 0.17 mL, 0.51 mmol) at ambient temperature. After 75 minutes, the mixture was partitioned between water (20 mL) and EtOAc (20 mL). The phases were separated and the organic phase dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica (eluant 35% EtOAc/isohexane). The material thus obtained was washed with hexane to afford the title compound as a white solid (53 mg). δH (500 MHz, d6 DMSO): 8.25 (1H, d, J 8.1), 7.71–7.64 (8H, m), 7.53 (1H, t, J 6.1), 7.40 (1H, d, J 16.4), 7.30–7.22 (3H, m), 4.98 (1H, s), 1.56 (6H, s). m/z (ES+) 419 [(M+Na)+].
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:35])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]([OH:34])=[O:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:43][CH3:44].O>CN(C)C=O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:35])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]([O:34][CH2:43][CH3:44])=[O:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C(=O)O)c1Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccn1-c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Yield: 103.4 %

Procedure:
A mixture of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-carboxypyrrole (1.12 g), potassium carbonate (360 mg) and iodoethane (490 mg). in N,N-dimethylformamide (10 ml) was stirred for 16 hours at 60° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, water and brine and dried over magnesium sulfate. The solvent was evaporated to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-ethoxycarbonylpyrrole (1.22 g) as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:9]([C:8]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=3[N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:10])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-morpholin-4-yl-5-nitro-benzoyl chloride and 4-chloro-phenyl-piperazine (orange solid), MS (m/e): 449.2 (M+H, 100%).