Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:6]=12.[C:18]([N:20]=[C:21]1[NH:25][CH2:24][CH2:23][S:22]1)#[N:19].C(N(CC)CC)C.CN(C)C=O>O>[C:18]([N:20]=[C:21]1[N:25]([C@@H:7]2[C:6]3[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH3:17])([CH3:16])[C@H:2]2[OH:1])[CH2:24][CH2:23][S:22]1)#[N:19]
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2C2OC21
Reactant: N#CN=C1NCCS1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
A mixture of 3,4-dihydro-3,4-epoxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (1.5 g), 2-(cyanoimino)-thiazolidine (1.1 g), triethylamine (3 ml) and N,N-dimethylformamide (6 ml) was stirred at 100° C. for 5 hours. After cooling, the reaction mixture was poured into water. The precipitate was collected by filtration, washed well with water and dried in vacuo to give trans-4-(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (1.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([CH3:41])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH2:28][N:29]([CH3:40])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH3:19])[C:12]1=[O:42].F[B-](F)(F)F.[N:48]1(OC(N(C)C)=[N+](C)C)[C:52]2C=CC=C[C:51]=2N=N1.C(N(C(C)C)C(C)C)C.C(N)C>CN(C=O)C.O>[C:34]1([CH2:33][O:32][C:30](=[O:31])[N:29]([CH2:28][CH2:27][O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:18]([NH:17][C:13]2[C:12](=[O:42])[N:11]([C:3]3[CH:4]=[C:5]([C:6]([NH:48][CH2:52][CH3:51])=[O:8])[CH:9]=[CH:10][C:2]=3[CH3:1])[CH:16]=[CH:15][N:14]=2)([CH3:19])[CH3:41])[CH3:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN(C)C(=O)OCc2ccccc2)c1=O
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCN(C)C(=O)OCc3ccccc3)c2=O)c1
Reaction time: 3 h
Yield: 750.1 %

Procedure:
To 4-methyl-3-[3-[[1-methyl-1-[2-[2-[methyl[(phenylmethoxy)carbonyl]amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid (Example 220d, 0.14 g) in DMF (3 mL) were added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.158 g) followed by N-ethyldiisopropylamine (0.212 mL) and the reaction stirred for 15 min before ethylamine (0.032 mL) was added and the reaction stirred for 3 h. The reaction was diluted with water and the aqueous layer extracted with ethyl acetate. The combined organics were dried (Na2SO4) and solvents removed in vacuo to give the subtitle product (1.10 g).
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:23]1[NH:24][C:25](=[NH:28])[S:26][CH:27]=1)[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl:36][CH2:37][C:38](Cl)=[O:39].C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:1]([O:4][N:5]=[C:6]([C:23]1[NH:24][C:25](=[N:28][C:38](=[O:39])[CH2:37][Cl:36])[S:26][CH:27]=1)[C:7]([O:9][CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=N)[nH]1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=NC(=O)CCl)[nH]1
Reaction time: 0.33 h

Procedure:
In 100 ml of N,N-dimethylformamide there were suspended 19.7 g of benzhydryl 2-acetoxyimino-2-(2-imino-4-thiazolin-4-yl)acetate, followed by the addition of 6.02 g of triethylamine. Under ice-cooling and stirring, 4.98 ml of chloroacetyl chloride were added dropwise. The mixture was further stirred at that temperature for 10 minutes and, then, at room temperature for 20 minutes. Thereafter, 1.50 ml of chloroacetyl chloride was added dropwise and the mixture were stirred for 20 minutes. The reaction mixture was poured into a solution of 4.4 g of sodium hydrogen carbonate in 200 ml of water and extracted with 500 ml of ethyl acetate in three installments. The ethyl acetate layers were pooled, washed twice with 100 ml of a 1e aqueous solution of sodium hydrogen carbonate and further washed with a saturated aqueous solution of sodium chloride. The drying with magnesium sulfate and the decolorization with activated carbon were concurrently carried out and, after filtering, the solvent was distilled off. To the residue there were added 20 ml of ethyl acetate and the mixture was allowed to stand. The resultant crystals were recovered by filtration and dried. By the above procedure there were obtained 12.7 g of benzhydryl 2-acetoxyimino-2-(2-chloroacetylimino-4-thiazolin-4-yl)acetate (syn-isomer). This product contained a small amount of the anti-isomer, which was removed by the following procedure.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:29](=[O:30])[CH:28]([CH3:32])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(C)C(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 73 %

Procedure:
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 2-methylpropionyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 73% yield.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]>C1COCC1>[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]
Reactant: C=CCCCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-(-)-4-benzyl-2-oxazolidinone (12.4 g, 69.79 mmol) in THF (200 mL) at −78° C. was added dropwise n-BuLi (30.7 mL, 2.5M solution in hexane, 76.77 mmol). After stirring for 30 min at the same temperature, the reaction mixture was then treated with 7-octenoyl chloride (11.21 g, 69.79 mmol). The reaction mixture was stirred and allowed to warm to 10° C. over 5 h, and then quenched with saturated aqueous NH4Cl solution (200 mL). The aqueous layer was extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine, and dried over MgSO4. Removal of the solvent under reduced pressure yielded the title compound. MH+302.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH2:35][CH3:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1.CN(C)C=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[C:1]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH2:35][CH3:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCON=C(C(=O)OCC)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 125.1 %

Procedure:
3.98 g of trityl chloride were slowly added under an inert atmosphere to a mixture of 3.16 g of the product of Step A, 6 ml of dimethylformamide, 12 ml of methylene chloride and 1.89 ml of triethylamine cooled to -15° C. and the mixture stood at 10° C. for 30 minutes and then 3 hours at room temperature. 13 ml of N hydrochloric acid were added to the mixture which was stirred and decanted. The organic phase was washed with N hydrochloric acid, then with water and was extracted with methylene chloride. The extracts were dried and evaporated to dryness to obtain 7.89 g of raw ethyl 2-(2-tritylamino-4-thiazolyl)-2-ethoxyiminoacetate having a syn configuration.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:15])([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:24][OH:25]>>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:24][O:25][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:15])([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cccc(F)c1F
Reactant: CCN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CCN1c2cc(OCc3cccc(F)c3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:17]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([NH2:17])([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)C=C1CN(C(=O)OC(C)(C)C)C1
Solvent: CCO
Product: COC(=O)CC1(N)CN(C(=O)OC(C)(C)C)C1

Procedure:
3-Methoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester (1.97 g; 8.7 mmol) in EtOH (20 ml) and liquid NH3 (11 g) are heated in a steel cylinder at 800 C for 6 hours. Evaporation of the solvent delivers the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 3.81 (d, 2H); 3.65 (s, 2H); 3.60 (d, 2H); 2.86 (s, 3H); 2.07 (bs, 2H); 1.43 (s, 9H). MS (m/z) ES+: 245 (100, MH+); 189 (90).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)cc1
Yield: 65.4 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′ (1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol), and 4-fluorophenyl boronic acid (0.72 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography; (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.70 g, 1.7 mmol, 67%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.42-1.77 (8H, m) 1.95-1.99 (2H, q) 5.00 (2H, s) 6.84 (1H, d, J=8.1 Hz) 7.21-7.63 (1H, m) 9.58 (1H, s); MS (ESI(−ve)) m/z 399 (M−H)−.
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[C:14]1[CH:20]=[C:19](O)C=[CH:17][C:15]=1O>CO>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:17][CH2:15][CH2:14][CH2:20][CH3:19]
Reactant: CCC=CCCCCCCCC
Reactant: Cc1cc(O)ccc1O
Solvent: CO
Product: C=CCCCCCCCCCCCCCCC
Reaction time: 17 h

Procedure:
8-methoxycarboniltetracyclo[4.4.0.12,5.117,10 ]-3-dodecen of 65 grams, dicyclopentadien of 87 grams and methylhydroquinon of 0.14 gram were mixed in a 300 milli-litter eggplant type flask, and the reaction was continued at 170 degrees to 180 degrees in centigrade for 17 hours. The reaction product remained cooled, and residual 8-methoxycarboniltetracyclo[4.4.0.12,5.117,10 ]-3-dodecen and residual dicyclopentadien were distillated in vacuum. Hot methanol was added to the residue, and insoluble content was filtrated. The filtrate was concentrated in vacuum, and residue was recrystallized from methanol. Then, we obtained white crystal of 12-methoxycarbonilhexacyclo[6.6.1.13,6.110,13.02,7.09,14 ]heptadecen of 10 grams.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:36](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:36][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=3)=[C:17]2[CH:16]=1.[C:3]1([N:24]([CH2:23][C:22]2[CH:21]=[CH:20][N:19]=[C:18]3[NH:36][C:15]([C:6]4[C:5]5[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:8]([CH3:14])[CH:7]=4)=[CH:16][C:17]=23)[C:25]2[CH:30]=[CH:29][C:28]([S:31][C:32]([F:34])([F:33])[F:35])=[CH:27][CH:26]=2)[CH:4]=[CH:5][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc2c(-c3cc4c(CNc5ccc(SC(F)(F)F)cc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CN(c5ccccc5)c5ccc(SC(F)(F)F)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Product: COc1cc2c(-c3cc4c(CNc5ccc(SC(F)(F)F)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 288.8 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylphenyl)amine is prepared as described in Example 179a starting with 0.08 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylphenyl)amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.53 cm3 of 5N potassium hydroxide. 0.068 g of phenyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylphenyl)amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](C=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN([CH:39]=[O:40])C>C(Cl)(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][N:1]2[C:9]3[C:4](=[C:5]([CH:39]=[O:40])[CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:25][CH2:26]1)=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCOS(C)(=O)=O)CC1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CCCCn2ccc3c(C=O)cccc32)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of 1H-indole-5-carbaldehyde (0.43 g, 2.96 mmol) in DMF (10 mL) was added NaH (60% in mineral oil; 0.14 mg, 3.55 mmol). After 45 min at 0° C., a solution of 4-(4-methanesulfonyloxy-butyl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.15 mmol) in DMF (5 mL) was added dropwise. The mixture was warmed to rt and stirred for 18 h. The mixture was diluted with CHCl3 (20 mL) and washed with water (15 mL). The organic layer was dried and concentrated to obtain the crude residue, which was used purified by FCC to give 0.96 g (88%). MS: mass calcd. for C22H30N2O3, 370.23; m/z found, 371.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH3:17])[CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].[CH2:18]([NH2:21])[CH2:19][NH2:20]>C(O)(C)C.O>[OH:1][CH:2]([CH3:17])[CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:20][CH2:19][CH2:18][NH2:21])(=[O:6])=[O:5]
Reactant: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCN
Solvent: O
Solvent: CC(C)O
Product: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCCN

Procedure:
28 g (0.1 mol) of 2-chloro-5-nitrophenyl 2-hydroxypropyl sulphone are refluxed in 100 ml of isopropanol. To this are added gradually 15 ml of ethylenediamine, and heating is continued with stirring for a further hour. The cold reaction solution is diluted with 300 ml of water and stirred at 20° C. for two hours. The precipitated yellowish crystals are filtered off with suction, washed with 100 ml of water and dried. This gives 28 g of uniform 2-(2-aminoethylamino)-5-nitrophenyl 2-hydroxypropyl sulphone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[CH:13]=[O:14].CC(=CC)C.Cl([O-])=[O:25].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[C:13]([OH:25])=[O:14]
Reactant: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
5-(3,4-dichlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde from Step 1 (492 mg, 0.001726 mol) and 2-methyl-2-butene (300 μL, 0.002832 mol) were stirred in tert-butyl alcohol (2.0 mL). A solution of sodium chlorite (400 mg, 0.003538 mol) and sodium dihydrogenphosphate (450 mg, 0.003751 mol) in water (3.0 mL) was added and reaction mixture was stirred for 12 hours at room temperature. Solvent was evaporated and resulting residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over MgSO4 and evaporated to give the title compound (340 mg, 65.5%) as white solid. This material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.O.[NH2:19][NH2:20]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:19][NH2:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: NN
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1cc(Cl)ccc1N)c1ccccc1F

Procedure:
In the manner given in Preparation 1, 2-amino-5-chloro-2'-fluorobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-5-chloro-2'-fluorobenzophenone hydrazone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])=[CH:5]2.C(N(CC)CC)C.[CH:35]12[CH2:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH:36]2[CH2:42][C:43](Cl)=[O:44]>C1COCC1.Cl>[CH:35]12[CH2:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH:36]2[CH2:42][C:43]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])=[CH:5]2)=[O:44]
Reactant: O=C(Cl)CC1CC2CCC1C2
Reactant: Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC1CC2CCC1C2)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, 78 mg (0.22 mmol) of 5-amino-N-phenyl-1-(2-phenylethyl)-1H-indole-2-carboxamide (Example LI) are dissolved in 2 ml of THF, and 24.4 mg (0.24 mmol) of triethylamine are added. The solution is cooled to 0° C., and a solution of 37.9 mg (0.22 mmol) of bicyclo[2.2.1]hept-2-ylacetyl chloride in 0.2 ml of THF is added dropwise. The reaction mixture is stirred at RT for 2 h and then diluted with 1-molar hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution and once with sodium bicarbonate solution, dried over sodium sulphate and filtered. The residue obtained after removal of the solvent under reduced pressure is purified chromatographically on silica gel (mobile phase: dichloromethane/ethyl acetate). 31.5 mg (29% of theory) of the product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]3[O:31][C:32](=[O:35])[NH:33][N:34]=3)[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:45]([CH3:47])[CH3:46].O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]3[O:31][C:32](=[O:35])[N:33]([CH:45]([CH3:47])[CH3:46])[N:34]=3)[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:25])([F:26])[C:21]([F:22])([F:23])[F:24])[N:9]=2)[N:7]=1
Reactant: CC1(c2n[nH]c(=O)o2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(C2(C)C(=O)Nc3nc(-c4nn(CCC(F)(F)C(F)(F)F)c5cc(Cl)ccc45)nc(N)c32)oc1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To the intermediate from Step A above (120 mg, 0.22 mmol) and finely powdered potassium carbonate (36.9 mg, 0.264 mmol) in DMF (3 mL), was added 2-iodopropane (35.9 mg, 0.21 mmol) and the reaction was stirred for 7 hours at room temperature. Water (4 mL) and ethyl acetate (15 mL) were then added to the reaction mixture. The water layer was extracted with ethyl acetate (3×). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by reverse phase HPLC to give the indicated compound as a white solid. Chiral separation using SFC on a Chiralcel OJ column provided both enantiomers of the title compound. 1H NMR (500 MHz, CDCl3) δ 1.31 (d, J=6.4 Hz, 3H); 1.33 (d, J=6.4 Hz, 3H); 1.77 (s, 3H); 2.84 (t, J=7.8 Hz, 2H); 4.36 (t, J=6.6 Hz, 1H); 4.78 (t, J=7.6 Hz, 2H); 5.34 (s, 2H); 7.27 (d, J=8.7 Hz, 1H); 7.49 (s, 1H); 8.51 (d, J=8.7 Hz, 1H). m/z=587.13 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]4)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]4)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CN1C(=O)CCc2cc(-c3cncc(C4=CCN(C(=O)OC(C)(C)C)CC4)c3)ccc21
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(C4CCN(C(=O)OC(C)(C)C)CC4)c3)ccc21
Yield: 82.4 %

Procedure:
5-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (example 247, 0.128 g, 0.305 mmol) in MeOH (50 mL) was run through the H-cube for 2 h (flow rate: 0.5 mL/min; temperature: 60° C.; catalyst: 10% Pd/C (THS 01111); full hydrogen mode). The resulting solution was evaporated to dryness to give the title compound (0.106 g, 74%) as a yellow amorphous solid. MS: 422.5 (M+H+).