Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH2:15]([CH:17]1[O:22][C:21]2[CH:23]=[C:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([O:41]CCCC)=[O:40])[CH2:34]4)=[N:31][CH:32]=3)[CH:25]=[CH:26][C:20]=2[N:19]([C:46](=[O:54])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:18]1)[CH3:16]>C(Cl)Cl>[CH2:15]([CH:17]1[O:22][C:21]2[CH:23]=[C:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34]4)=[N:31][CH:32]=3)[CH:25]=[CH:26][C:20]=2[N:19]([C:46](=[O:54])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:18]1)[CH3:16]
Reactant: CCCCOC(=O)CC1CCN(c2ncc(-c3ccc4c(c3)OC(CC)CN4C(=O)Nc3ccccc3)cn2)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1CN(C(=O)Nc2ccccc2)c2ccc(-c3cnc(N4CCC(CC(=O)O)C4)nc3)cc2O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
Trifluoroacetic acid (0.109 mL, 1.43 mmol) and triethylsilane (44 μL, 0.28 mmol) were successively added at room temperature to a solution of crude ted-butyl 2-(1-(5-(2-ethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidin-3-yl)acetate B-8 (59.0 mg, 0.11 mmol) in anhydrous methylene chloride (0.25 mL) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 12 h, then concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-(1-(5-(2-ethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidin-3-yl)acetic acid B-9 (22.3 mg, Yield=42% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01 (t, J=Hz, 3H), 1.63-1.74 (m, 3H), 2.12-2.18 (m, 1H), 2.42 (d, J=7.25 Hz, 2H), 2.52-2.64 (m, 1H), 3.15 (dd, J=7.88, 10.88 Hz, 1H), 3.46 (dd, J=7.88, 12.60 Hz, 1H), 3.48 (t, J=7.56 Hz, 1H), 3.63-3.69 (m, 1H), 3.80 (dd, J=7.41, 11.35 Hz, 1H), 4.03 (br d, J=13.08 Hz, 1H), 4.16 (q, J=6.69 Hz, 1H), 7.00 (t, J=7.41 Hz, 1H), 7.15 (br d, J=8.67 Hz, 1H), 7.18 (s, 1H), 7.29 (t, J=7.41 Hz, 2H), 7.50 (d, J=8.36 Hz, 2H), 7.51 (d, J=8.83 Hz, 1H), 8.66 (s, 2H), 9.14 (s, 1H), 12.22 (br s, 1H); MS (ESI) [M+1]+ 488.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)c(OC)c1
Yield: 67.3 %

Procedure:
Using 1.56 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane, 1.80 g of 1-(2,4-dimethoxyphenyl)piperazine dihydrochloride, 1.9 ml of triethylamine and 50 ml of dioxane, reaction and workup were carried out as in Example 1-A. Purification by column chromatography (silica gel, elution with ethyl acetate:hexane =1:0.5) gave 1.96 g of pale red crystals, m.p. 110-112° C.
Reaction SMILES: C(O[C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.[O:27]1C2C(=CC=CC=2)C(O)CC1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[O:16]1[C:11]2[C:12](=[CH:25][CH:26]=[CH:9][CH:10]=2)[C:13](=[O:27])[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15]1
Reactant: OC1CCOc2ccccc21
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1c(-c2ccccc2)coc2ccccc12

Procedure:
Using the general procedure of hydroboration-oxidation, compound 1 was converted into a chroman-4-ol (compound 4) at a yield of 60%. Compound 4 was treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in refluxing 1,4-dioxane to undergo oxidation-dehydrogenation to give an isoflavone (compound 5) at a yield of 78%. After the deprotection of compound 5 with AlCl3/EtSH, daidzein (compound 6a) was produced at a yield of 92%. On the other hand, compound 5 could be selectively debenzylated with Pearlman's reagent to give formononetin (compound 6b) at a yield of 94%,
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[N:20][C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:22][C:17]=3[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N:23]1([C:21]2[N:20]=[CH:19][C:18]3[C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][NH:16][C:17]=3[CH:22]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3cc(N4CCOCC4)ncc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1[nH]c2cc(N3CCOCC3)ncc2c1C1CCNCC1
Yield: 100.1 %

Procedure:
4-(6-Morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (380 mg, 0.98 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated. The residue was dissolved in MeOH (20 mL) and neutralized with DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure to give 281 mg (100%) of a yellow solid. MS (electrospray): exact mass calculated for C16H22N4O, 286.18; m/z found, 287.1 [M++H].
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[NH:6][C:7]([CH:9]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:10][CH2:11][C:12](O)=[O:13])=[N:8][C:4]=2[CH:3]=1.CN(C(O[N:42]1N=NC2C=[CH:46][CH:47]=[CH:48][C:43]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CCCC1.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[NH:6][C:7]([CH:9]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:10][CH2:11][C:12]([N:42]3[CH2:43][CH2:48][CH2:47][CH2:46]3)=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc(C(=O)NC(CCC(=O)O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(CCC(=O)N2CCCC2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 54 %

Procedure:
Prepared analogously to Example 1g from rac.-N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, and pyrrolidine in tetrahydrofuran. Yield: 54%; Rf value: 0.22 (silica gel; ethyl acetate/ethanol=9:1); C28H32ClN5O3 (522.05); mass spectrum: (M+H)+=522/524 (chlorine isotope).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1.[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH2:13][CH:14]3[CH2:23][CH2:22][N:21]4[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:15]3)=[O:11])=[CH:2]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: BrCC1CCCCC1
Product: O=C(OCC1CCN2CCCCC2C1)c1cn(CC2CCCCC2)c2ccccc12

Procedure:
eq-Quinolizidin-2-ylmethyl indole-3-carboxylate (E9b) was alkylated with cyclohexylmethyl bromide using the method of Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford a colourless oil, which crystallised from n-pentane to give the title compound (E29) as a white solid mp 98°-100° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]=2[CH3:1])=[O:18])[CH:22]=[CH:23][C:24]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)#[N:27]
Reactant: N#Cc1cc(N)ccc1OCCCN1CCOCC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)Nc2ccc(OCCCN3CCOCC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 42.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (1.0 g) synthesized according to Starting Material Synthesis Example 88 and 5-amino-2-(3-morpholinopropoxy)benzonitrile (0.9 g), the title compound (0.75 g) was obtained, melting point: 172–174° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH3:15])[CH:8]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:2][C:1]([CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH3:15])[CH:8]=1)=[O:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(OCCC(=O)O)ccc1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCC(=O)OCc2ccccc2)ccc1C=O
Reaction time: 8 h

Procedure:
To a suspension of 4-(2-carboxyethoxy)-2-methyl-benzaldehyde (7.2 g) and potassium carbonate (14.3 g) in N,N-dimethylformamide (70 mL) was added benzyl bromide (8.2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1) to give the title compound (6.47 g).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH:26](OC)OC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CN(C=O)C>C1C=CC=CC=1>[C:1]([N:9]1[C@@H:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:17][CH:24]1[O:25][CH3:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1OC(OC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Preparation of the title compound was conducted on a larger scale as follows. [R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (3.138 g) was suspended in benzene (100 ml), and trimethoxymethane (3.190 g) and PPTS (628 mg) were added. The reaction solution was heated to reflux, 20 ml of DMF were added for dissolution of most of the starting compound, followed by heating with a Soxhlet extractor. The thimble in the extractor was filled with 4 Å mol. sieves. After 1 hour, and approximately 3 to 4 cycles in the Soxhlet extractor, TLC showed consumption of the starting material, and a new major spot of the title product. It was diluted with EtOAc, washed with NaHCO3 and H2O, dried and the solvent removed. NMR showed the presence of the title product and a small impurity. The product was purified on HPLC (hexane:ethyl acetate, 3:1) to give 3.138 g (97%) of the title product. The product (an oil) was a mixture of diastereomers (not separated).
Reaction SMILES: O1CCO[CH:2]1[C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>C(O)C.O.Cl>[NH2:12][C:11]1[C:6]([CH:2]=[N:13][NH:14][C:15]([NH2:17])=[S:16])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccnc1C1OCCO1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=S)NN=Cc1ncccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1,3-dioxolanyl)-3-aminopyridine (0.80 g, 4.8 mmol) in 10 mL of ethanol, 8 mL of water and 2 mL of concentrated hydrochloric acid was added 0.48 g (5.3 mmol) of thiosemicarbazide. The mixture was stirred at room temperature overnight and refluxed for 1 h, cooled and filtered. The crude yellow hydrochloride salt was dissolved in 50 mL of hot water and filtered. To the hot filtrate was added 10 mL of 5% sodium bicarbonate solution. The mixture was stirred at room temperature for 1 h, filtered and washed with water, followed by ethanol to yield 3-amino-2-formylpyridine thiosemicarbazone. Yield: 0.72 g (77%); mp 240°-241° C. dec; MS m/e 194 (M+); 1H NMR (90 MHz, DMSO-d6) δ 6.48 (br s, 2H, 3-NH2, D2O exchangeable), 7.12 (m, 2H, 4-H and 6-H), 7.83 (dd, 1H, 5-H), 8.10 (br s, 2H, CSNH2, D2O exchangeable), 8.10 (s, 1H, 2-CH), 10.95 (s, 1H, NNH, D2O exchangeable). Anal. (C7H9N5S) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=CC(CN2CCOCC2)=CC=1.BrC1C=C2C(=CC=1)[C:36](=[O:40])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:40][CH3:36]
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(CN2CCOCC2)cc1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 5.11 g (81.9% yield) of yellow solid is obtained from 4.0 g (14.18 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 3.24 g (17.0 mmol) of 4-[(2-methylpyrrolidin-1-yl)methyl]phenyl}amine: mp 183-184° C.; MS (ESI) m/z 440.0 (M+H)+1
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:54]1[CH:59]=[CH:58][C:57]([CH2:60][NH:61][C:62]([CH:64]2[CH2:69][CH2:68][CH2:67][CH:66]([NH:70][C:71]3[N:76]=[C:75]([CH3:77])[N:74]=[C:73]([NH:78][CH3:79])[N:72]=3)[CH2:65]2)=[O:63])=[C:56]([Cl:80])[CH:55]=1.[NH:81]1[CH2:86][CH2:85][CH2:84][CH2:83][CH2:82]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:80][C:56]1[CH:55]=[C:54]([N:81]2[CH2:86][CH2:85][CH2:84][CH2:83][CH2:82]2)[CH:59]=[CH:58][C:57]=1[CH2:60][NH:61][C:62]([C@H:64]1[CH2:69][CH2:68][CH2:67][C@@H:66]([NH:70][C:71]2[N:76]=[C:75]([CH3:77])[N:74]=[C:73]([NH:78][CH3:79])[N:72]=2)[CH2:65]1)=[O:63]
Reactant: C1CCNCC1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)NCc3ccc(Br)cc3Cl)C2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(N4CCCCC4)cc3Cl)C2)n1
Temperature: 100 °C

Procedure:
In a microwave reaction vessel was added cesium carbonate (0.049 g, 0.150 mmol) under nitrogen. Next, Pd2(dba)3 (4.89 mg, 5.34 μmol), BINAP (4.99 mg, 8.02 μmol), N-[(4-bromo-2-chlorophenyl)methyl]-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (0.050 g, 0.107 mmol) and piperidine (10.58 μl, 0.107 mmol) were then added to the reaction vial. Toluene (4.00 ml) was added and the reaction was heated to 100° C. for 16 hours. LCMS showed the formation of the desired product and the consumption of the starting materials. The reaction was cooled, the solvent was removed under vacuum, and the residue was purified by preparative HPLC to provide cis-N-{[2-chloro-4-(1-piperidinyl)phenyl]methyl}-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (19 mg, 0.032 mmol, 30%). MS (ES+): m/e 472, 474 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:36](=[CH2:40])[CH2:37][CH2:38][OH:39].C1COCC1>CCOC(C)=O.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O>[Cl:1][C:2]1[C:7]([C:36]([CH2:37][CH2:38][OH:39])=[CH2:40])=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25]
Reactant: C=C(Br)CCO
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(B2OC(C)(C)C(C)(C)O2)c1Cl
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(CCO)c1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Temperature: 60 °C
Yield: 43 %

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (864 mg, 2.282 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride (84 mg, 0.114 mmol), and potassium phosphate, dibasic (1192 mg, 6.85 mmol) were added to a 100 ml flask, and the flask was purged with N2. 3-bromobut-3-en-1-ol (0.226 mL, 2.282 mmol) and THF (12 mL) were added, followed by water (2.182 mL). The reaction was heated at 60° C. for 1 h. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, then brine, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-50% EtOAc/Hex; 120 g column). Tert-butyl (2-chloro-5-cyano-3-(4-hydroxybut-1-en-2-yl)phenyl)carbamate (317 mg) was obtained as a colorless glass.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:28]#[N:29])=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=3)[N:14]2[CH2:17][CH3:18])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:28]#[N:29])=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=3)[N:14]2[CH2:17][CH3:18])=[CH:10][CH:9]=1
Reactant: CCOc1ccc(-c2c(C#N)c3ccc(NC(=O)OC(C)(C)C)cc3n2CC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(-c2c(C#N)c3ccc(N)cc3n2CC)cc1
Yield: 96 %

Procedure:
Compound 832 prepared in step A above (0.63 g, 1.56 mmol) is treated with TFA/DCM (7.5 mL/7.5 mL) at room temperature for 2 h, and the volatiles are removed in vacuum. The residue is treated with saturated NaHCO3 and the precipitate is collected via filtration and washed thoroughly with water, dried in air to provide 6-amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.45 g, 96%), compound 833.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH3:18])=[O:25])=[CH:15][CH:16]=1
Reactant: CSc1ccc(C(=O)Nc2c(C)cccc2C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1NC(=O)c1ccc(S(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Ten grams of N-(2,6-dimethylphenyl)-4-(methylthio)benzamide were dissolved in a small volume of chloroform and chilled to 0° C. A solution of 7.9 g of m-chloroperoxybenzoic acid in chloroform was added in dropwise fashion. The reaction was stirred at room temperature for 1 hour, washed with a sodium bicarbonate solution, water, and a saturated chloride solution, dried over sodium sulfate and evaporated in vacuo. The resulting foam was chromatographed over silica gel eluting with an ethyl acetate in hexane gradient. The appropriate fractions were combined and the solvent removed in vacuo and the resulting residue was crystallized from ethyl acetate/hexane providing the desired title product in 59% yield, m.p. 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(OC(=O)C)C>[Cl:1][C:2]1[C:3]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=2[S:5][C:6]=1/[CH:7]=[CH:18]/[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1sc2ccc(Cl)cc2c1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])C/C=C/c1sc2ccc(Cl)cc2c1Cl
Temperature: 90 °C

Procedure:
In a sulfonation flask, a mixture containing 6.93 g (0.03 mol) 3,5-dichlorobenzo[b]thio-phene-2-carbaldehyde, 18 g (0.24 mol) nitroethane, 5.8 g (0.075 mol) ammoniumacetate and 60 ml acetic acid is heated at 90° C. for 6 hours. After cooling ethylacetate is added and the organic phase washed three times with water. The organic phase is dried over sodium sulphate and after filration the organic solvent is distilled off in a water jet vacuum. The residue is purified by column chromatography over silicagel (eluent: ethylacetate/heptane 1:5). After chromatography further purification via crystallisation from ethylacetate could be achieved. Yield: 4 g (47% of theory). M.p. 143°-146° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:19]([C:18]3[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:17]=3[O:16][CH:13]([CH3:15])[CH3:14])=[O:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1Cl)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(Cl)c(Cl)c2C1

Procedure:
Prepared in analogy to example 1.1 from 7,8-dichloro-1,2,3,4-tetrahydro-isoquinoline (CA [61563-24-4]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[S:7][C:6]([C:8](OC)=[O:9])=[CH:5][CH:4]=1.CO.[BH4-].[Na+]>C1COCC1>[F:1][CH:2]([F:12])[C:3]1[S:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(C(F)F)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of methyl 5-(difluoromethyl)thiophene-2-carboxylate (2.23 g) in THF (60 ml)-MeOH (15 ml) was added NaBH4 (2.20 g) at room temperature, and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.94 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9]([N:12]1[CH:17]=[CH:16][C:15](=[N+](C)C)[CH:14]=C1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][S:9]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (3 g; 9.955 mmol) prepared according to the procedure from Winum et al (Organic Letters 2001, 3, 2241) in DCM (24 mL) was treated with pyrrolidine (0.864 mL; 10.453 mmol) and stirred at rt for 24 h. The reaction mixture was chromatographed by FC on silica gel (eluent: CH2Cl2/EtOAc 100:1) to give [N-(tert-butoxycarbonyl)]-pyrrolidine-1-sulfonic acid amide. TLC: Rf (DCM/EtOAc 100:1)=0.40. A solution of [N-(tert-butoxycarbonyl)]-pyrrolidine-1-sulfonic acid amide (57.09 g; 223 mmol) in DCM (450 mL) was treated with TFA (120 mL; 1.56 mol) and stirred at rt for 7 h. The reaction mixture was concentrated in vacuo and the residual oil was triturated with diisopropylether. The resulting powder was washed with diisopropylether and dried under high vacuum to provide Compound 1a. TLC: Rf (DCM/EtOAc 50:1)=0.10.