Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3].[C:35](Cl)(=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][N:31]([CH2:32][CH3:33])[C:35](=[O:44])[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)CCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester, hydrochloride and hydrocinnamoyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.Br[CH:16]([Si](C)(C)C)[S:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.C1C=CC=CC=1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:14])[C@H:10]3[C@@H:18]([Si:19]([CH3:22])([CH3:21])[CH3:20])[S:17][CH2:16][C@H:11]3[C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1c1cccc(Br)c1
Reactant: C[Si](C)(C)CSC(Br)[Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)[C@H]1SC[C@H]2C(=O)N(c3cccc(Br)c3)C(=O)[C@H]21
Temperature: 110 °C

Procedure:
A flask was charged with 1-(3-bromo-phenyl)-pyrrole-2,5-dione (800 mg, 3.17 mmol) and bromo-trimethylsilanyl-trimethylsilanylmethylsulfanyl-methane (1.36 g, 4.76 mmol, [literature compound)) in dry DMF (3 ml) under nitrogen atmosphere. The material was heated at 110° C. (oil bath) for 2 hours and then cooled to ambient. The solvent was stripped (rotovap/pump) and the remainder taken up in benzene (30 ml) and brine (30 ml). The material was shaken and the organic phase collected. The aqueous phase was back-extracted with benzene (2×20 ml) and the organic phases combined, dried (MgSO4), filtered and stripped. The crude was purified by chromatography on silica gel eluting with 5% to 40% EtOAc in hexanes, providing 1.04 g of (3S,3aS,6aR)-5-(3-bromo-phenyl)-3-trimethylsilanyl-tetrahydro-thieno[3,4-c]pyrrole-4,6-dione as a light white-yellow solid.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)=[CH2:2].[CH3:12][Si](Cl)(C)C>CO>[CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: C[Si](C)(C)Cl
Reactant: C=C[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CO
Product: C=C[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 25 °C

Procedure:
All of trans-4-vinyl cyclohexane carboxylic acid was dissolved in 120 mL of methanol and 0.1 g of trimethylsilyl chloride was added, followed by refluxing for 6 hours. The solution was cooling to room temperature and then concentrated under reduced pressure. 150 mL of hexane was added and the methanol layer was separated, and then the methanol layer was extracted with hexane. After combining with the organic layer, the mixture was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to obtain 29.5 g of methyl trans-4-vinylcyclohexanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:4]([CH:3]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 5 °C
Yield: 96.8 %

Procedure:
To a 500 ml, 4-necked flask fitted with a stirrer, thermometer, addition funnel and reflux condenser is charged sulfuric acid (50 ml) and methyl m-fluorobenzoate (8.5 g, 0.055 mole). The reaction mixture is then cooled to 5° C. and a solution of potassium nitrate (reagent 5.57 g, 0.055 mole) is concentrated sulfuric acid (50 ml) is added dropwise over a 30 minute period. Ten minutes after completion of addition the reaction mixture is poured onto 500 g of cracked ice and the product extracted into benzene (3×100 ml). The combined benzene extracts are dried with anhydrous magnesium sulfate and the filtrate reduced in vacuo to give 10.6 g (96%) of product, which is a yellow liquid. Anal. Calcd. for C8H6FNO4 : C, 48.20; H, 3.04; F, 9.54; N, 7.02. Found: C, 50.15; H, 3.34; F, 9.17; N, 6.77.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:23]2[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: Cc1cc(C)cc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3,5-dimethylbenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([C@H:4]([O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1)[CH3:5])([OH:3])=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51]>>[C:50]([NH:49][CH2:48][CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:40][C:1]([C@H:4]([O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:8]1)[CH3:5])=[O:3])(=[O:52])[CH3:51]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O[C@H](C)C(=O)O)cc1
Reactant: CC(=O)NCCc1ccccc1N
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O[C@H](C)C(=O)Nc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Example 3a, 0.165 g of tert-butyl 3-(1(R)-carboxyethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.066 g of N-[2-(2-aminophenyl)ethyl]acetamide (Example 34c) are reacted. The title compound is obtained as a yellow oil. Rf=0.22 (95:5 dichloromethane-methanol); Rt=5.34.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=2)=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)c1cccc(F)c1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 3-fluorobenzoic acid.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C@H:8]([NH:23][C:24]([O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.CO>[CH:30]1[C:29]2[CH:28]([CH2:27][O:26][C:24]([NH:23][C@H:8]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:10])[CH2:7][C:6]([OH:41])=[O:5])=[O:25])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CCCCCCCCCCCNC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCCCCCCCCNC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 99.3 %

Procedure:
A solution of (S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-N-undecylsuccinamic acid tert-butyl ester (113 mg, 0.2 mmol) in TFA (2 ml) was stirred at room temperature for 30 min. After completion of the reaction, TFA was removed by evaporation in vacuo. Purification of the residue by silica gel column chromatography (using dichloromethane:methanol=9:1 as an eluent) gave (S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-N-undecylsuccinamic acid (101 mg, 99% yield) as a colorless amorphous solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:18]=2)=[C:7]1[CH3:32])C.C1(S(C2C=CC=CC=2CC2C3C(=CC=C(F)C=3)N(CC(O)=O)C=2C)(=O)=O)CCCCC1>>[F:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:33])=[O:3])[C:7]([CH3:32])=[C:8]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)(=[O:24])=[O:25])[CH:18]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2cccc(S(=O)(=O)N3CCCCC3)c2)c2cc(F)ccc21
Agent: Cc1c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Product: Cc1c(Cc2cccc(S(=O)(=O)N3CCCCC3)c2)c2cc(F)ccc2n1CC(=O)O

Procedure:
2-(5-fluoro-2-methyl-3-(3-(piperidin-1-ylsulfonyl)benzyl)-1H-indol-1-yl)acetic acid ethyl ester was used as a starting material, otherwise this compound was prepared in a similar manner to Compound 1, using Procedure L.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([F:22])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](=[O:37])[C:27](=[CH:33]OCC)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24]>C1(C)C(C)=CC=CC=1>[CH:1]1([N:4]([CH:33]=[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:37])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]2[CH:6]=[CH:7][C:8]([F:22])=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:10]=2)[CH2:2][CH2:3]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2F)CC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(=CN(c1ccc(F)c(N2CCN(C(=O)OCC)CC2)n1)C1CC1)C(=O)OCC
Yield: 39.1 %

Procedure:
A solution of 3.8 g (12.3 mmole) of 4-[6-(cyclopropylamino)-3-fluoro-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 2.7 g (12.3 mmole) of diethyl(ethoxymethylene)malonate and 50 ml of xylene was refluxed for 24 hours. The solvent was removed in vacuo and the residue was chromatographed over silica gel eluting with chloroform/ethyl acetate (80/20) to give 2.3 g of the title compound as a viscous oil which was used without further purification.
Reaction SMILES: NC1C=CC=CC=1S.CN(C)C1C=CC(C=O)=C([N+]([O-])=O)C=1.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][C:33]=1[N+:41]([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>Cl>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:39])[CH3:40])=[CH:34][C:33]=1[NH2:41]
Reactant: CN(C)c1ccc(-c2nc3ccccc3s2)c([N+](=O)[O-])c1
Agent: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Product: CN(C)c1ccc(-c2nc3ccccc3s2)c(N)c1
Reaction time: 0.5 h

Procedure:
Starting from 2-aminothiophenol and 4-dimethylamino-2-nitro-benzaldehyde, (4-benzthiazol-2-yl-3-nitro-phenyl)-dimethylamin is prepared in analogy to the procedure described in example 1 of DE-A-2333378. b) In a 250 ml three-necked flask equipped with magnetic stirrer, thermometer, reflux condenser and nitrogen inlet, 15.25 g of (78.8 mmol) anhydrous tin(II) chloride are dissolved in 40 ml of 37% hydrochloric acid, and 6.94 g (23.2 mmol) of (4-benzthiazol-2-yl-3-nitro-phenyl)-dimethylamin (product of part a) are added with stirring. The thick, red suspension heats up to 100° C. The internal temperature is kept at 60° C. for the following 5 hours. After cooling, the reaction mixture is adjusted to pH 14 by addition of 180 ml of a 4N solution of sodium hydroxid, and stirring is continued for another 30 minutes. After filtration, the residue is washed three times with 50 ml of water and dried over night at 50° C. and 25 mbar, yielding 6.49 g of crude 4-benzthiazol-2-yl-N,N-dimethyl-benzene-1,3-diamin, which is used for the subsequent step without further purification. c) Into a 250 ml three-necked flask equipped with magnetic stirrer, thermometer and nitrogen inlet, 6.20 g (23.0 mmol) of crude 4-benzthiazol-2-yl-N,N-dimethyl-benzene-1,3-diamin (product of part b) in 65 ml of pyridine are introduced and cooled to 3° C. with stirring. 3.19 g (27.6 mmol) of methansulfochloride are added dropwise within 30 Minuten using a syringe, then the ice bath is removed and the black solution is stirred over night at room temperature. The reaction mixture is then poured dropwise into 700 ml of ice water; the reddish brown suspension thus obtained is stirred for 20 minutes, filtered, the residue washed 3 times with 100 ml of ice water, and dried over night at 50° C. and 25 mbar. 7.50 g of the title product are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(OC1C=CC(Br)=NC=1)C1C=CC=CC=1.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:49]1[CH2:52][CH:51]([NH:53][C:54](=[O:71])[CH2:55][NH:56][C:57]2[C:66]3[C:61](=[CH:62][CH:63]=[C:64]([C:67]([F:70])([F:69])[F:68])[CH:65]=3)[N:60]=[CH:59][N:58]=2)[CH2:50]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:49]3[CH2:50][CH:51]([NH:53][C:54](=[O:71])[CH2:55][NH:56][C:57]4[C:66]5[C:61](=[CH:62][CH:63]=[C:64]([C:67]([F:68])([F:70])[F:69])[CH:65]=5)[N:60]=[CH:59][N:58]=4)[CH2:52]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(c2ccc(O)cn2)CC1
Agent: Brc1ccc(OCc2ccccc2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccc(O)cn3)CC2)C1

Procedure:
Reaction of 4-(5-hydroxypyridin-2-yl)cyclohexanone (prepared by the reaction of 5-(benzyloxy)-2-bromopyridine with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[Li]C(C)(C)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C:16]1([CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]1)[C:15]2=[N:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:18]([CH2:17][C:16]3([CH2:21][CH2:22][CH:23]([O:26][CH3:27])[CH2:24][CH2:25]3)[C:15]2([NH:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[C:1]([O:3][CH2:4][CH3:5])=[CH2:2])=[CH:19][CH:20]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Reactant: C=COCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 0 °C
Yield: 89 %

Procedure:
To solution of ethyl vinyl ether (1) (269 mg, 357 μL, 3.73 mmol, 5 eq.) in dry THF (10 mL) chilled to −78° C. under N2 was added 1.7 M t-BuLi in heptanes (1.75 mL, 2.98 mmol, 4 eq.) dropwise within 10 min. The temperature of the resulting yellow clear solution1 was allowed to warm to 0° C. slowly within 30 min. By removing dry ice and adding water to dry ice-acetone bath, finally the cooling bath was replaced with a ice water bath. The color changed from yellow to nearly colorless after being stirred ca 5 min at 0° C. Then the lithium regent solution (2) was cooled to −78° C. again and cannulated to a solution of starting material 4 (307.5 mg, 0.746 mmol) in dry THF (5 mL) at −78° C. with positive pressure. The resulting mixture was stirred at this temperature for another 30 min. The reaction was quenched with saturated aqueous NH4Cl and extracted with ether and EA, the combined organic phases were washed with water and brine, dried, and filtered. The solvent was removed under reduced pressure to generate off-white foam, which was purified by flash chromatography on silica gel 9:1 eluted with EA in hexane (0-40%) to produce the desired product 5 and its diastereomers in a ratio (321 mg, yield 89%). MS ESI+ve m/z 484 (M+H)30.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:69](=O)([O-])[O-:70].[Cs+].[Cs+].CO>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([Cl:37])[C:34]([O:70][CH3:69])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1Cl)N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O
Yield: 37 %

Procedure:
Combine isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.050 g, 0.079 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.0014 g, 0.0015 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.002 g, 0.0047 mmol), cesium carbonate (0.039 g, 0.119 mmol) and methanol (0.016 mL, 0.397 mmol) in toluene (1 mL) in a sealed tube and heat at 110° C. for 24 h. Dilute the cooled mixture with ethyl acetate (25 mL) and filter through Celite. Remove the filtrate solvent under reduced pressure and first purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a white solid (0.017 g, 37%): ESI MS 581 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1)=[O:10]>C(O)(=O)C.[Fe]>[NH2:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:17][CH:14]2[CH2:13][CH2:12][N:11]([C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[O:10])[CH2:16][CH2:15]2)[CH:23]=1
Reactant: O=C(c1c(F)cccc1F)N1CCC(Oc2cc([N+](=O)[O-])ccn2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccnc(OC2CCN(C(=O)c3c(F)cccc3F)CC2)c1
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
Add powered iron (419 mg, 7.5 mmol) to a solution of 1.1 g (3.0 mmol) of (2,6-difluoro-phenyl)-[4-(4-nitro-pyridin-2-yloxy)-piperidin-1-yl]-methanone, in glacial acetic acid (10 mL) and stir at 80° C. After 15 min, allow the mixture to reach room temperature and filter through Celite®. Wash the Celite® pad with Et2O and EtOAc. Wash the resulting organic layer with water, a saturated aqueous NaHCO3 solution and a saturated aqueous sodium chloride solution. Separate organic layer, dry over MgSO4 and evaporate solvents to afford 831 mg (83% yield) of title compound as a white solid. (ES+(m/z)=334 [M+H].
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([CH:11]=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O1CCCC1>>[C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([CH:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[OH:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1oc(C(C)(C)C)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)cc1C(O)C1CCCCC1
Yield: 62 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-tert-butyl-2-methyl-3-furaldehyde (2.5 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (23 mL) to give the title compound (2.3 g, 62%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7](/[CH:13]=[N:14]/[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[C:3]=1[C:4]([OH:6])=O.[CH3:26][Li].Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4](=[O:6])[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[CH:13]([CH3:26])[C:7]=2[C:8]([F:12])=[C:9]([Cl:11])[N:10]=1
Reactant: COc1ccc(C/N=C/c2c(F)c(Cl)nc(Cl)c2C(=O)O)c(OC)c1
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2C)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
To a mixture of (E)-2,6-dichloro-4-(((2,4-dimethoxybenzyl)imino)methyl)-5-fluoronicotinic acid (72.0 g, 186.5 mmol) in THF (700 mL) was added methyllithium (933.0 mL, 933.0 mmol) dropwise at −78° C. After the addition was complete, the solution was stirred for an additional 2 h. The reaction mixture was then acidified with 1N HCl to pH 6, heated to 50° C. for 7 h, and subsequently extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4. The concentrated crude was purified by silica gel chromatography to give the title compound as a white solid (14 g, 15%). 1H NMR (CDCl3, 400 MHz) δ ppm 1.58 (d, J=6.8 Hz, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 4.35 (d, J=14.4 Hz, 1H), 4.52 (q, J=6.8 Hz, 1H), 5.07 (d, J=14.4 Hz, 1H), 6.43-6.45 (m, 2H), 7.28 (d, J=9.2 Hz, 1H). [M+H] calc'd for C17H15Cl2FN2O3, 385. found, 385.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10](=[CH:14][O:15][CH2:16][CH3:17])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([O:25][CH2:26][CH3:27])=[CH:23][CH3:24])[CH3:20].CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:10]2[C@@H:14]([O:15][CH2:16][CH3:17])[C@H:23]([CH3:24])[C:22]([O:25][CH2:26][CH3:27])([O:21][CH2:19][CH3:20])[O:13][C:11]=2[CH3:12])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(Cl)cc1
Reactant: CC=C(OCC)OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCO[C@@H]1C(C(=O)Nc2ccc(Cl)cc2)=C(C)OC(OCC)(OCC)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(4'-Chlorophenyl)-2-ethoxymethylene-3-oxo-butanamide (1.3 g) and tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedianato)ytterbium (0.26 g) were stirred in toluene (10 ml) whilst 1,1-diethoxyprop-1-ene (2 g) was added dropwise. The mixture was stirred at room temperature for two hours and evaporated to dryness. The residual gum was purified by medium pressure liquid chromatography on K60 silica using ethyl acetate/petroleum ether b.p. 60°-80° C., 15/85 v/v as eluting solvent to give two stereoisomers. The first isomer after trituration with n-hexane gave trans-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (0.2 ), m.p. 104°-106° C. The second isomer, again after trituration with n-hexane, gave cis-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (1.3 g), m.p. 125°-127° C.