Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])O.C(O)(=O)C=C>>[C:1]([OH:6])(=[O:5])[CH:2]=[CH2:4].[C:1]([O:6][CH3:7])(=[O:5])[CH:2]=[CH2:4]
Reactant: COC(=O)C(C)O
Agent: C=CC(=O)O
Product: C=CC(=O)OC

Procedure:
Efficient dehydration of methyl lactate to acrylic acid using Ca3(PO4)2—SiO2 catalyst by Jong-Min Lee et. al (Catalysis Communications, Volume 11, Issue 15, 25 Sep. 2010, Pages 1176-1180) describes a series of catalysts consisting of Ca3(PO4)2 supported on SiO2 (silicate, colloidal silica and fumed silica) and Ca3(PO4)2—SiO2 (silicate) with different loadings of Ca3(PO4)2 (70 to 95 wt. %) was prepared by sol-gel and wet-impregnation methods. All the catalysts were found to be active in the vapor phase dehydration of methyl lactate (ML) to give mainly acrylic acid (AA), methyl acrylate (MA). Among the catalysts, Ca3(PO4)2—SiO2(silicate) of (80:20 wt. %) was found to be an efficient catalyst in the dehydration of Methyl Lactate, which gave 73.6% conversion of Methyl Lactate with selectivity for Acrylic Acid and Methyl Acrylate together (77.1%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][SH:18])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[OH-].[Na+].O.[Cl:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>C(O)C>[ClH:3].[ClH:24].[ClH:1].[ClH:3].[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][S:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([CH2:8][C:7]4[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:28][CH2:29]2)=[CH:35][CH:36]=1
Reactant: ClCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1ccc(CN2CCN(CCCSCCN3CCN(Cc4ccc(Cl)cc4)CC3)CC2)cc1
Yield: 96.5 %

Procedure:
A mixture of 3-[4-(4-chlorobenzyl)piperazine-1-yl]propanethiol dihydrochloride (2 g), sodium hydroxide (0.3 g), water (10 ml), and ethanol (100 ml) is refluxed for 15 minutes, and then a solution of 1-(2-chloroethyl)-4-(4-chlorobenzyl)piperazine (1.9 g) in ethanol (20 ml) is added. The resulting mixture is refluxed for 2 hours and the ethanol is removed in vacuo. Water is added to the residue and the product is extracted with methylene chloride, dried (magnesium sulfate), and concentrated. The resulting oil is purified on a silica gel column (methylene chloride: methanol, 9:1), and then dissolved in ether. The product is precipitated with ethereal hydrochloric acid and recrystallized from aqueous ethanol to provide 1.2 g of {2-[4-(4-chlorobenzyl)piperazin-1-yl)ethyl}{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}sulfide tetrahydrochloride as colorless crystals, m.p. 292°-295° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:13]([CH2:15]P(=O)(OCC)OCC)#[N:14].[H-].[Na+]>O1CCCC1>[C:13]([CH2:15][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1)#[N:14]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCCc1ccc(S(N)(=O)=O)cc1

Procedure:
For the preparation of the amine starting material of Example 24, p-aminosulfonylbenzaldehyde was reacted with diethyl cyanomethylphosphonate/sodium hydride in tetrahydrofuran to give 1-cyano-2-(4-aminosulfonylphenyl)-ethane which was hydrogenated in methanol with Raney-cobalt as the catalyst to give 3-(4-aminosulfonylphenyl)-propylamine.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CN1CCOCC1.[NH2:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35]([NH2:37])=[O:36]>CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35]([NH2:37])=[O:36])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)[C@H](N)C(N)=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 66 h
Yield: 75.3 %

Procedure:
4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride 13 (0.45 g, 1.19 mmol) was dissolved in dry DMF (5 mL), and added to a solution of N-methylmorpholine (3 mL) and (2S)-amino-3-methylbutyramide (0.18 g, 1.19 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 66 h. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) to give the desired product 14 as a white powder (0.41 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.72 (d, 3H), 0.76 (d, 3H), 1.77 (m, 4H), 1.79 (m, 1H), 2.68 (m, 2H), 3.40 (m, 1H), 3.60 (m, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.34 (d, 2H) 7.50 (d, 1H), 7.65 (d, 2H), 7.82 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=1)([O-:3])=[O:2].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O>CS(C)=O>[CH3:14][O:13][C:6]1[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: COc1c(C(=O)O)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
4-Nitro-2-methoxybenzoic acid, 3.09 g, was added to 20 mL Nitric acid:Sulfuric acid 1:1, at 0° C. After addition was complete the reaction mixture was heated at 100 ° C. for 30 minutes. Cooled to room temperature and poured into 200 mL ice water. The aqueous layer was extracted with ethyl acetate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. This material was purified by chromatography on silica using ethyl acetate/hexane/methanol/acetic acid 5/5/1/0.1. The yellow solid obtained was used for the next step. EIMS M+ 242 (Exp. 242). NMR, d6 DMSO: s (1H) 8.5, s (1H) 7.95, s (3H) 4.05.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:47][CH2:50][NH:51][C:52](=[O:54])[CH2:53]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(F)nc2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccc(F)nc3)n2)CCN1

Procedure:
50 mg (0.11 mmol) of the compound of Example 42A is reacted analogously to the synthesis of the compound of Example 1 with 12 mg (0.12 mmol) of 2-oxopiperazine. 51 mg (85% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5](=[N:24][C:25]1[CH:36]=[CH:35][C:28]([C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])=[CH:27][CH:26]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)[CH:7]=1.O>COCOC.COCCOC>[CH3:1][S:2][C:5](=[N:24][C:25]1[CH:36]=[CH:35][C:28]([C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])=[CH:27][CH:26]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)[CH:7]=1
Reactant: C[S-]
Reactant: C=CCOC(=O)c1ccc(N=C(Cl)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Na+]
Solvent: COCOC
Solvent: COCCOC
Solvent: O
Product: C=CCOC(=O)c1ccc(N=C(SC)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a round bottom flask, 700 mg (10 mmoles) of sodium thiomethylate are suspended in 25 ml of dimethoxymethane. At ambient temperature and under a nitrogen stream, there are slowly introduced 3.5 g (7.6 mmoles) of allyl 4-[α-chloro-3-(1-adamantyl)-4-methoxybenzylideneamino]benzoate obtained in Example 4(b) and dissolved in 50 ml of DME. After 3 hours of reaction, the mixture is poured into water and extracted with ethyl ether. The organic phase is dried on sodium sulfate, then evaporated under a vacuum; the resulting crude product is chromatographed on a silica column eluted with a 20/80 mixture of ethyl ether and hexane. After evaporation of the solvents 2.6 g (73%) of the expected product whose melting point is 50°-53° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([C@H:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1
Reactant: CC(C)C(C)n1cc(Br)c2[nH]nc(N)c2c1=O
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)[C@H](C)n1cc(Br)c2[nH]nc(N)c2c1=O
Yield: 47.5 %

Procedure:
Racemic 3-amino-7-bromo-5-(3-methylbutan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G of Example 13 (7.89 g) was resolved by HPLC (column: CHIRALPAK AD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=600/400(v/v)) to give the title compound (3.751 g) having a shorter retention time.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](OC)(OC)[CH3:6].[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].[BH4-].[Na+].[Cl-].[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.Cl.C(OCC)(=O)C.CO.C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C@@H:5]([NH:17][S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[CH3:6]
Reactant: COCCC(C)(OC)OC
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC[C@H](C)N[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.9 %

Procedure:
1,3,3-Trimethoxybutane (145.4 g, 0.98 mol) is combined with 1 N aqueous hydrochloric acid (50.0 mL, 0.05 mol) and stirred for 1-2 h at RT under a nitrogen atmosphere. THF (1.5 L) is added and the solvent is evaporated at standard atmospheric pressure below 70° C. twice. THF (1.5 L) is added to prepare a solution of 4-methoxybutan-2-one in THF. (S)-(−)-2-Methyl-2-propanesulfinamide (124.4 g, 1.03 mol) and titanium (IV) ethoxide (447.0 g, 1.96 mol) are added and the reaction heated to 65-70° C. for 16-17 h. The reaction mixture is cooled to −10 to 0° C. Sodium borohydride (37.0 g, 0.98 mol) is added in portions, and then the mixture is stirred for 1-2 h at the same temperature. The reaction mixture is warmed to RT and stirred for 1-2 h. It is then cooled to 10-20° C. and methanol (100 mL) is added dropwise over 1-2 h. 25% Aqueous sodium chloride (300 mL) is added and the mixture is warmed to RT. Ethyl acetate (500 mL) is added. The mixture is stirred for 1-2 h at RT and then filtered. The filtercake is rinsed with additional ethyl acetate (807 mL). The layers are separated and the organic phase is washed with 25% aqueous sodium chloride (1.0 L). The aqueous phase is extracted with ethyl acetate (500 mL). The organic portions are combined, and the solvent is distilled at atmospheric pressure (no vacuum) below 75° C. to arrive at a solution of 300-500 mL total volume. Ethyl acetate (600 mL) and sodium thiosulfate (150.0 g) are added and the mixture is stirred for 1-2 h at 20-30° C. The mixture is filtered and the filtrate is concentrated. The diastereomers are separated by supercritical fluid chromatography to afford the title compound as a yellow oil (205.0 g, 65%). Column. ChiralPak® AD 10 μm, 50×300 mm; Elution mode: Isocratic; Mobile phase: CO2/ethanol; Flow rate: 280 mL/min; UV detection: 215.16 nm; Loading: 300 mg/mL. The first eluting peak is the minor diastereomer, TR=15.17 min. The second eluting peak is the major diastereomer representing the title compound, TR=17.11 min.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])C(=O)C2=CC=CC=C12>C(O)C.O.NN>[NH2:5][CH2:6][CH2:7][P:8](=[O:15])([O:9][CH2:10][CH3:11])[O:12][CH2:13][CH3:14]
Reactant: CCOP(=O)(CCN1C(=O)c2ccccc2C1=O)OCC
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOP(=O)(CCN)OCC
Reaction time: 16 h

Procedure:
A mixture of 4.67 g (0.015 mol) of diethyl phthalimidoethylphosphonate in 30 ml of ethanol and 1.2 ml of 100% hydrazine hydrate is kept at ambient temperature for ca. 16 hours then is refluxed for 2 hours. The mixture is cooled and filtered and the filtrate is concentrated to give diethyl (2-aminoethyl)phosphonate.
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32][OH:33])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32][O:33][S:37]([CH3:36])(=[O:39])=[O:38])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of 164 (840 mg, 1.709 mmol), methansulfonyl chloride (160 μA, 2.051 mmol) and DIPEA (448 μl, 2.56 mmol) in DCM is stirred at RT under nitrogen overnight. The solution is partitioned between DCM and water, then the aqueous phase is extracted with DCM. The combined organic phases are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give the title compound (774 mg, 80% yield).
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.[CH2:58]([C:60]1[CH:70]=[CH:69][C:63]([O:64][CH2:65][CH2:66][CH2:67]Cl)=[C:62]([O:71][CH3:72])[CH:61]=1)[CH3:59].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[CH2:58]([C:60]1[CH:70]=[CH:69][C:63]([O:64][CH2:65][CH2:66][CH2:67][N:48]2[CH2:47][CH2:46][CH:45]([C:43]([C:51]3[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=3)([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[OH:44])[CH2:50][CH2:49]2)=[C:62]([O:71][CH3:72])[CH:61]=1)[CH3:59]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CCc1ccc(OCCCCl)c(OC)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CCc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1
Yield: 74.7 %

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(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 3-(4-ethyl-2-methoxyphenoxy)propyl chloride, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 3.7 g (74%) of title compound as a white solid, mp 118°-120° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[O:16][C:15]([C:17](=[NH:21])OCC)=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].CO[CH:24](OC)[CH2:25][NH2:26].CO>Cl>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[O:16][C:15]([C:17]3[NH:21][CH:24]=[CH:25][N:26]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COC(CN)OC
Reactant: CCOC(=N)c1ccc(-c2ccc(OC)c(OC)c2)o1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc(-c3ncc[nH]3)o2)cc1OC
Yield: 28.3 %

Procedure:
A mixture of 52.0 g (0.167 mole) of ethyl 5-(3,4-dimethoxyphenyl)-2-furimidate hydrochloride, 19.3 g (0.184 mole) of aminoacetaldehyde dimethyl acetal and 800 ml of anhydrous methanol was heated to reflux with dissolution. The solution was refluxed for 5 hours and the solvent was then removed on the Calab evaporator yielding a residual oil which was stirred in 800 ml of 3N HCl for ca. 20 hours at a temperature of 70°. The resulting solid was washed in refluxing acetic acid, filtered hot and dried at 100° to yield 14.5 g (28%) of 2-[5-(3,4-dimethoxyphenyl)-2-furyl]imidazole hydrochloride. An analytical sample was prepared by washing a sample a second time in refluxing acetic acid and drying in the vacuum piston at the temperature of refluxing water, m.p. 288°-289°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH:14]=[CH:13][C:12]([NH2:15])=[N:11]1.[Na+].[I-].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:12]2[NH:11][N:10]=[CH:14][CH:13]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Nc1cc[nH]n1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To the solution of 2,4-dichloro-6-methylpyrimidine (3.00 g) and 1H-pyrazol-3-amine (1.31 g) in NMP (30 mL) was added NaI (2.36 g) and DIEA (6.33 mL). And the mixture was heated to 80° C. under stirring. After 1 day, the mixture was cooled to room temperature. The mixture was diluted with Et2O. The precipitate was collected by filtration, washed with the mixed solvent of hexane and EtOAc and dried in vacuo to give 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine (2.60 g) as a pale yellow solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[C:14]2[N:13]=[C:12]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([C:24]3[N:25]=[C:26]([CH3:36])[S:27][C:28]=3[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[O:23])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].O>CO>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]2[S:27][C:26]([CH3:36])=[N:25][C:24]=2[C:22]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[CH2:15][C:12]2[NH:11][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[C:14]=3[N:13]=2)=[O:23])=[CH:34][CH:33]=1
Reactant: CC(=O)c1cccc2[nH]c(CC3CCCCN3C(=O)c3nc(C)sc3-c3ccc(F)cc3)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(C(C)O)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium borohydride (145 mg) was added portionwise over 2 min. to a cooled (0-10° C.) solution of (RS)-1-[2-(4-acetyl-1H-benzimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone, E68 (365 mg) in methanol (10 ml). After stirring for a further 2.5 h at room temperature, water (100 ml) was added and the mixture was extracted with dichloromethane (2×). The combined organics were dried (Na2SO4), evaporated and the residue chromatographed (silica gel, 0-100% ethyl acetate-hexane then 2-10% methanol-ethyl acetate) to afford the title compound as a solid (320 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 104.1 %

Procedure:
To a solution of 4-fluorophenylacetic acid (1, scheme 1) (26.5 g, 172 mmol) in DCM (93 mL) was added oxalyl chloride (2 eq., 30.1 mL, 344 mmol) over 5 min and DMF (0.005 eq., 0.067 mL, 0.86 mmol) over 1 min. The reaction mixture was stirred at r.t for 2 h then concentrated. The residual DCM was removed as an azeotrope with toluene (2×20 mL) to afford intermediate 2-(4-fluorophenyl)acetyl chloride (1a) (30.85 g, 179 mmol, assumed quantitative yield) as yellow oil. Part of that material was used as is in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][Se:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([NH:41][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[Se:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(C[Se]c2ccccc2C(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C[Se]c2ccccc2C(=O)Nc2ccccc2)cc1

Procedure:
To a solution of 1.58 g (0.00517 mol) 2-(4-methylbenzylseleno)benzoic acid (example 2) and 0.58 g (0.00573 mol) triethylamine in 10 ml dichloromethane which has been cooled to 0° C. is added 1.32 g (0.00517 mol) solid bis[2-oxo-3-oxazolidinyl]phosphoryl chloride in one portion. After stirring for 30 minutes a solution of 0.48 g aniline (0.47 ml; 0.00517 mol) in 10 ml dichloromethane and 0.74 g (1.02 ml; 0.00573 mol) triethylamine in 10 ml dichloromethane is added dropwise with stirring. The reaction mixture is stirred for 20 hours at room temperature and treated with 20 ml distilled water. The organic phase is separated and extracted successively with 20 ml water, two 25 ml portions of 10% hydrochloric acid and two 25 ml portions of 10% sodium hydroxide solution and dried. The solvent is then removed and the residue purified by column chromatography (silica gel/dichloromethane).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][C:11]1[C:12]([CH3:23])=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:19]3[CH:20]=[CH:21][C:16]([C:15]4[O:14][N:13]=[C:12]([CH3:23])[C:11]=4[CH2:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:24])=[CH:17][CH:18]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)OCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)OCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid benzyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:13]=2[CH2:12][NH:11]1.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[CH3:26][S:23]([N:11]1[CH2:12][C:13]2[C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:10]1)(=[O:25])=[O:24]
Reactant: COC(=O)c1cccc2c1CNC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2c1CN(S(C)(=O)=O)C2
Yield: 51.4 %

Procedure:
DIEA (0.438 g, 3.39 mmol) was added to a solution of methyl isoindoline-4-carboxylate (0.5 g, 2.82 mmol) and mesyl chloride (0.36 g, 3.1 mmol) in DCM (10 mL). After 12 h the mixture was concentrated and the residue purified by silica gel chromatography to afford methyl 2-(methylsulfonyl)isoindoline-4-carboxylate (0.37 g 52%) as an off white solid.