Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H](C(O)=O)C(C)(C)C.[BH4-].[Na+].[CH3:12][C:13]1[CH:32]=[CH:31][C:16]2[NH:17][C:18](=[O:30])[C:19](=[O:29])[CH:20]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[S:21][C:15]=2[CH:14]=1.C(O)(=O)C.O1CCCC1>O1CCCC1>[OH:29][C@@H:19]1[C:18](=[O:30])[NH:17][C:16]2[CH:31]=[CH:32][C:13]([CH3:12])=[CH:14][C:15]=2[S:21][C@@H:20]1[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(C2Sc3cc(C)ccc3NC(=O)C2=O)cc1
Agent: CC(C)(C)[C@@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2Sc3cc(C)ccc3NC(=O)[C@H]2O)cc1
Temperature: -15 °C
Reaction time: 0.42 h
Yield: 80.6 %

Procedure:
A mixture of D-tert-leucine (721 mg), sodium borohydride (189 mg) and tetrahydrofuran (50 ml) is refluxed under nitrogen atmosphere for three hours. The mixture is cooled to -15° C., and thereto is added a solution of 8-methyl-2-(4-methylphenyl)-1,5-benzothiazepine-3,4(2H, 5H)-dione (991 mg) in tetrahydrofuran (3 ml). Each 0.38 ml of 25% acetic acid/tetrahydrofuran solution (1.67 mmole as acetic acid) is added thereto at 25 minutes, and 2 hours 10 minutes after the beginning of the reaction, and the reaction solution is stirred at the same temperature for 20 hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added 1N hydrochloric acid (70 ml). The precipitated crystal is collected by filtration, washed with water, and dried. The collected crystal is suspended in isopropyl alcohol (12 ml), and the mixture is heated with stirring at 80° C. for three hours. The mixture is cooled to 5° C., and allowed to stand for five hours. The precipitated crystal is collected by filtration, washed with cold isopropyl alcohol, and dried to give (2R,3R)-3-hydroxy-8-methyl-2-(4-methylphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (804 mg).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:16][C:17](=[O:20])[C:18]#[CH:19])[CH3:15].C(OC(=O)C=CN(C1CCCCC1)C1CCCCC1)C.[F:41][C:42]1[C:50]([F:51])=[C:49]([F:52])[C:48]([F:53])=[CH:47][C:43]=1[C:44](Cl)=[O:45].[NH2:54][N:55]([CH3:58])[CH:56]=[O:57]>C1(C)C=CC=CC=1.ClCCl>[CH2:14]([O:16][C:17](=[O:20])[C:18]([C:44](=[O:45])[C:43]1[CH:47]=[C:48]([F:53])[C:49]([F:52])=[C:50]([F:51])[C:42]=1[F:41])=[CH:19][NH:54][N:55]([CH:56]=[O:57])[CH3:58])[CH3:15]
Reactant: C#CC(=O)OCC
Reactant: CN(N)C=O
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCOC(=O)C=CN(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(=CNN(C)C=O)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.3 %

Procedure:
A solution of 1.81 g (10 mmol) of dicyclohexylamine was added to a solution of 0.98 g (10 mmol) of propiolic acid ethyl ester in 4 ml of toluene, and the mixture was stirred for 6 hours at room temperature. The resulting yellow solution of 3-(dicyclohexylamino) acrylic acid ethyl ester was heated to 100° C., 0.98 g (9.6 mmol) of triethylaimine were added and the mixture heated to reflux. With stirring a solution of 1.93 g (9.1 mmol) of 2,3,4,5-tetrafluorobenzoic acid chloride in 10 ml of toluene was added in the course of 10 min. The brown suspension was filtered hot and the filter residue washed twice with 15 ml of toluene. The united filtrates containing the so formed 3-(dicyclohexyl-amino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylic acid ethyl ester were stirred for 160 hours at room temperature with 7.41 g (100 mmol) of N-amino-N-methylformamide. The resulting brown suspension was dissolved in 200 ml of dichloromethane, extracted with 50 ml of 1N aqueous hydrochloric acid, and the aqueous extracts washed twice with each 50 ml of dichloromethane. The organic phases were united, dried over magnesium sulphate, filtered and evaporated at 45° C./30 torr. The light-brown, oily residue (4.65 g) was suspended in 10 ml of tert.-butyl methyl ether, digested intensely for 30 min., the crystals filtered, washed twice with each 5 ml of tert.-butyl methyl ether and dried at 25° C./33 torr. There were obtained 1.91 g (64%) of 3-(2-formyl-2-methylhydrazino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylic acid ethyl ester as a white powder of mp 189°.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:31]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1)[CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: NC1CCCC1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C(C)=O)C1CCCC1

Procedure:
{2′-[(Acetyl-cyclopentyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-31) was prepared according to the procedures outlined in Example 1 by using the following materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester, cyclopentylamine and acetyl chloride.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH2:23]([C@H:30]([CH2:41][C:42]([CH2:44]Cl)=[O:43])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([C@H:30]([CH2:41][C:42](=[O:43])[CH2:44][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)SCC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 73 %

Procedure:
To tert-butylmercaptan (0.11 ml) in dimethylformamide (5 ml) at 0° C. was added potassium bis(trimethylsilyl)amide in toluene (1.80 ml, 0.90 mmol, 0.5M) followed by the resultant compound from Example 34 (259.6 mg, 0.785 mmol) in dimethylformamide (3 ml). After 16 h at room temperature the mixture was diluted with ethyl acetate, washed with water and brine, then dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with 10% ethyl acetate in hexane afforded 219.6 mg (73%) of a colorless oil. 1H NMR (CDCl3) δ7.10-7.40 (m,10H), 5.07 (s,2H), 3.25 (s,2H), 3.18-3.29 (m,1H), 2.97-3.07 (m,2H), 2.78 (dd,1H), 2.71 (dd,1H), 1.25 (s,9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([O:14][CH3:15])[C:11]([OH:13])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([O:14][CH3:15])[C:11]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([C:17]#[N:16])=[CH:19][CH:20]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc2c(c1)OCO2
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc2c(c1)OCO2

Procedure:
(RS)-Benzo[1,3]dioxol-5-yl-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-benzo[1,3]dioxol-5-yl-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow solid.
Reaction SMILES: C(N1C(=O)C(COS(C)(=O)=O)=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)C.[C:28]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([C:45]([O:47]C)=[O:46])[C:37](=[O:44])[N:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:39]=2)=[CH:30][CH:29]=1>>[C:28]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:29]=[CH:30][C:31]([C:34]2[CH:35]=[C:36]([C:45]([OH:47])=[O:46])[C:37](=[O:44])[N:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:39]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(-c2ccc(-c3ccccc3)cc2)nn(CC(C)C)c1=O
Agent: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(C(=O)O)c1=O
Yield: 79.2 %

Procedure:
Following the procedure of Example 1 (7), 6-(4-biphenylyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a colorless crystalline powder (yield: 79.2%).
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([CH3:16])[O:15][C:3]=12.[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:23]([CH3:38])[C:24]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]3)=[N:25][N:26]=1>>[ClH:17].[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[N:23]([CH3:38])[C:24]([C:27]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]5)=[N:25][N:26]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([CH3:16])[O:15][C:3]=12
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Reactant: Cc1nc2cc3c(c(Br)c2o1)CCNCC3
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C)oc6c(Br)c5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 10-bromo-2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (52 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (73 mg) and was obtained as a colourless slightly hygroscopic solid (48 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([C:6](=[O:19])[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[O:9]2)=[CH:4][CH:3]=1.[CH2:20]([C:23]1[C:33]([OH:34])=[C:32]([C:35](=[O:37])[CH3:36])[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:21][CH3:22]>>[C:15]([C:8]1[O:9][C:10]2[C:5]([C:6](=[O:19])[CH:7]=1)=[CH:4][CH:3]=[C:2]([O:1][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:30]=[CH:31][C:32]([C:35](=[O:37])[CH3:36])=[C:33]([OH:34])[C:23]=1[CH2:20][CH2:21][CH3:22])[C:11]=2[CH2:12][CH2:13][CH3:14])([O:17][CH3:18])=[O:16]
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2ccc3c(=O)cc(C(=O)OC)oc3c2CCC)ccc(C(C)=O)c1O
Yield: 69 %

Procedure:
Using the procedure of Example 2, 5.25 g (120 mmole) of methyl 7-hydroxy-8-n-propylchromone-2-carboxylate and 6.93 g (22 mmole) of the compound of Example 14 gave 7.54 g (76%) of the title compound, mp. 113°-115°. Calc: C, 67.73; H, 6.50; Found: C, 67.71; H, 6.49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH:14]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:18]3[CH2:19][CH2:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]3[CH:14]([CH3:16])[CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(C)C1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC(C)C1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Isopropyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:4][CH:5](I)[CH3:6])(=[O:3])[CH3:2].[Cl:8][C:9]1[C:10]([F:49])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])=[O:36])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:9]1[C:10]([F:49])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([O:44][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])=[O:36])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)I
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(C)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a mixture of the above 1-iodoethyl acetate (311 mg, 1.457 mmol) and chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (US20100152190A1, 201.7 mg, 0.327 mmol) in dimethylformamide (6 mL) was added cesium carbonate (659 mg, 2.00 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was taken up in ethyl acetate, washed with water and then brine. The organic layer was dried over sodium sulfate and concentrated to dryness. The crude material was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 20/80) to give 1-acetoxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (149.4 mg, 65% yield). MS (ES+) m/z calcd. for C35H36Cl2F2N3O6: [(M+H)+]: 702.19, found: 702.4
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[F:28][C:29]1[C:34](O)=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39]>ClCCl>[F:28][C:29]1[C:34]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N#CC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CC(C(=O)Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1
Reaction time: 4 h

Procedure:
8 g. (0.05 moles) of α-cyano-phenylacetic acid are dissolved in dichloromethane. Under mild heating 10.3 g. (0.05 moles) of dicyclohexylcarbodiimide and 0.2 g. (0.05 moles) of pentafluorophenol dissolved in 50 ml. of dichloromethane are added dropwise. The mixture is stirred for 4 hours at 30° to 35° C. It is cooled, and the precipitated dicyclohexylurea is filtered. The substance on the filter is washed twice with 10 ml. of dichloromethane. The combined organic layers are evaporated while petrolether is added. The crystalline ester is precipitated from petrolether.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:27])[CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[CH3:28][Mg]Br>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([CH2:9][C:8](=[O:27])[CH3:28])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:12]=2)[CH:15]=1
Reactant: C[Mg]Br
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Sc2ccccn2)cc1
Product: CC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-thioacetic acid S-pyridin-2-yl ester 1c and methyl magnesium bromide (MeMgBr) using a similar procedure described above. 1H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H), 2.31 (s, 3H), 2.38 (s, 3H), 4.08 (s, 2H), 7.03 (d, J=9.1 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 7.54 (m, 4H). Mass spectrum m/e 279 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:13])[NH:10][CH2:11]Cl)[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([OH:21])=[O:20].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:9]([NH:10][CH2:11][O:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:15]=1[Cl:14])=[O:13]
Reactant: O=C(NCCl)Oc1cccc(Cl)c1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(COc1ccc(Cl)cc1Cl)OCNC(=O)Oc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
A solution of 220.1 g (1 mole) of N-chloromethylcarbamic acid 3-chlorophenyl ester in 1 liter of anhydrous ethyl acetate was added dropwise at 0° to 10° C to a mixture of 221 g (1 mole) of 2,4-dichlorophenoxyacetic acid and 111.3 g (1.1 moles) of triethylamine in 2 liters of ethyl acetate. The mixture was stirred for a further 15 hours at 20° C and was cooled to 5° C, and the triethylammonium chloride which had precipitated was filtered off. The filtrate was washed neutral with water and was concentrated in vacuo by distilling off the solvent. The solid residue was recrystallised from ether. 290 g (71.8% of theory) of 2-(2,4-dichlorophenoxy)-acetic acid 3-chlorophenoxycarbonylaminomethyl ester were obtained in the form of white crystals of melting point 110° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([O:14][CH2:15][CH3:16])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH2:15]([O:14][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]([CH3:13])=[C:2]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH2:26][CH2:27]2)[C:3]=1[CH3:17])[CH3:16]
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Product: CCOc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 22.6 %

Procedure:
By using 5-bromo-7-ethoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (500 mg, 1.67 mmol) synthesized in Reference example 98 and 1-(4-methylphenyl)piperazine (589 mg, 3.34 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 149 mg (yield 23%).
Reaction SMILES: C([O:5][CH2:6][CH:7]([O:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])(C)(C)C.ClCCl.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH:20]([O:19][CH2:18][CH2:17][O:16][CH:7]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])[CH2:6][OH:5])([CH3:22])[CH3:21]
Reactant: CC(C)OCCOCC(COC(C)(C)C)OCCOC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)OCCOCC(CO)OCCOC(C)C

Procedure:
Compound 32 was prepared as described for 29. The reagents used were as follows, compound 26 (g, mol.), tetrafluoroboric acid-diethyl ether complex ml of a 54% solution in diethyl ether), dichloromethane (100 ml) and excess potassium carbonate. the final yield was a colorless liquid (g, %), (bpt. °C., torr.): 1H-NMR (CDCl3), d, (ppm). Mass spectroscopy, m/e M+.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C1COCC1>[CH3:13][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][O:14]1
Reactant: CC(=O)c1ccccc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of acetophenone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C([O-])=O.[NH4+]>CCO.O.CCOC(C)=O.[Fe]>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Cc1ccc(N)cc1
Temperature: 90 °C
Yield: 38.6 %

Procedure:
To a mixture of 1-(methylsulfonylmethyl)-4-nitrobenzene (1.5 g, 7 mmol) in EtOH (20 mL) and H2O (10 mL) was added iron (1.96 g, 35 mmol) and ammonium formate (4.41 g, 70 mmol). After heating at 90° C. for 2 h, it was diluted with EtOAc, washed with saturated NaHCO3, brine, dried and concentrated to give 4-(methylsulfonylmethyl)aniline (0.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8]([C:12]3[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=3[O:23][CH3:24])=[N:9]2)=[CH:5][N:4]=1.[CH3:25][NH2:26]>>[CH3:1][O:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8]([C:12]3[CH:17]=[C:16]([S:18]([NH:26][CH3:25])(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=3[O:23][CH3:24])=[N:9]2)=[CH:5][N:4]=1
Reactant: CN
Reactant: COc1ncc2[nH]c(-c3cc(S(=O)(=O)Cl)c(Cl)cc3OC)nc2n1
Product: CNS(=O)(=O)c1cc(-c2nc3nc(OC)ncc3[nH]2)c(OC)cc1Cl

Procedure:
Prepared analogously to Example 11 from 2-methoxy-8-(2-methoxy-4-chloro-5-chlorosulfonyl-phenyl)-purine and aqueous methylamine solution.
Reaction SMILES: [Cl-].[OH:2][C:3]1[C:4]([CH3:18])=[N+:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)S(O[C:25]1[CH:30]=[CH:29]C=[CH:27][C:26]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].O.[CH3:40]C#N>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:5]2[CH:6]3[C:29]4[CH:30]=[CH:25][CH:26]=[CH:27][C:18]=4[C:4]2([CH3:40])[C:3](=[O:2])[CH:8]=[CH:7]3)=[CH:11][CH:12]=1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(C[n+]2cccc(O)c2C)cc1
Reactant: CC#N
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: COc1ccc(CN2C3C=CC(=O)C2(C)c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of compound 73 (11.97 g) in CH3CN (125 mL) was added 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (75) (30 g) and CsF (20 g). The mixture was stirred at room temperature for 3 days. Water was added to quench the reaction and most of the CH3CN was removed via rotavaporator. The residue was extracted with EtOAc, washed with water and brine, and dried over MgSO4. After concentration of the solvent, the crude product was purified by silica gel chromatography, eluting with a gradient of 100% hexane to 80% EtOAc/hexane over 30 min. The pure product was isolated as a brown oil. 1H NMR (CDCl3) δ 7.30-7.24 (m 3H), 7.21-7.15 (m, 3H), 7.01 (dd, 1H, J=5.1, 9.6 Hz), 6.87 (d, 2H, J=8.7 Hz), 5.62 (d, 2H, J=9.6 Hz), 4.31 (d, 1H, J=5.1 Hz), 3.81 (s 3H), 1.65 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[O:12]=[C:13]1[CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:29]2[CH2:30][CH2:31][CH2:32][C@@H:28]2[C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][C:13]3=[O:12])=[CH:24][CH:23]=2)=[O:27])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)C1CCCN1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CCCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 95 mg (0.61 mmol) of 4-chlorophenyl isocyanate are added to a solution of 200 mg (0.61 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-carboxamide hydrochloride and 1 ml of triethylamine in 5 ml of methylene chloride, and the reaction solution is stirred at room temperature for two hours. The reaction solution is subsequently washed with 5 ml of 1N hydrochloric acid and 5 ml of water, and the methylene chloride solution is dried over sodium sulfate. After the solvent has been stripped off under reduced pressure, the crude product is recrystallised from ethanol/diethyl ether, giving 120 mg of the title compound (“A1”) as a white powder; ESI 443; m.p. 227.6°.