Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1>C(O)C>[Cl:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: CCOC(=O)CCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 92.8 %

Procedure:
Analogously to Example 1a, 30 g (0.3 mol) ethyl acrylate and 63.2 g 1-(4-chlorobenzyl)-piperazine are reacted in 200 ml ethanol to give 86.5 g (92.8% of theory) ethyl 3-[4-(4-chlorobenzyl)-piperazin-1-yl]-propionate; b.p. 150° - 160° C./0.1 mm Hg.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][CH:10]([OH:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:12][CH:10]([CH3:11])[CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1
Reactant: CC(O)CBr
Reactant: O=Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(O)Cn1cc(C=O)cn1
Temperature: 150 °C

Procedure:
Combine 1H-pyrazole-4-carbaldehyde (0.150 g, 1.56 mmol), racemic 1-bromo-2-propanol (0.260 g, 1.87 mmol), and potassium carbonate (0.323 g, 2.34 mmol) in acetonitrile (2 mL). Heat in microwave at 150° C. for 20 min. Filter, wash with acetonitrile and concentrate filtrate. Purify via silica gel chromatography, eluting with 0:100 to 100:0 ethyl acetate:hexanes) to give the title preparation (177 mg, 73%). GC-MS: m/z=154 [M+].
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]#[N:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.O[Li].O>C1COCC1.O>[C:16]([CH2:15][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3])#[N:17]
Reactant: CCOC(=O)c1cc2ccccc2n1CC#N
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#CCn1c(C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
To a solution of 1.0 eq. of 1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester in a mixture of THF/H2O ((9/1) was added LiOH.H2O (1.0 eq.) and the reaction mixture stirred 6 h at RT, acidified to pH2 and then partially concentrated until precipitation of the crude product which was filtered off and washed with Et2O and then dried to give the desired product as a light yellow solid (70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:45])[CH2:42][CH2:43][NH2:44]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][N:41]([CH3:45])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 71.2 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (15 mg, 0.027 mmol) in DCM (5 mL) was added N,N-dimethyl-1,2-ethanediamine (0.009 mL, 0.083 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (11 mg, 72%).
Reaction SMILES: [ClH:1].O=[C:3]([CH3:23])[CH2:4][C:5]1[CH2:6][N:7]([CH3:22])[CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]=12.[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C([BH3-])#N.[Na+]>CO>[ClH:1].[ClH:1].[CH:24]([NH:27][CH:3]([CH3:23])[CH2:4][C:5]1[CH2:6][N:7]([CH3:22])[CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]=12)([CH3:26])[CH3:25]
Reactant: COc1ccc2c(c1)CCC1CCN(C)CC(CC(C)=O)=C21
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC1CCN(C)CC(CC(C)NC(C)C)=C21

Procedure:
The solution of 0.84 g of 1-(2-oxopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepine hydrochloride, 1.28 ml of isopropylamine, 0.66 ml of 4.4 N methanolic hydrochloric acid and 0.17 g of sodium cyanoborohydride in 13 ml of methanol is refluxed overnight. Additional 0.085 g of sodium cyanoborohydride are added and the whole is again refluxed for 5 hours. The mixture is cooled, acidified to pH=1 with concentrated hydrochloric acid and the methanol evaporated. The aqueous solution is washed with diethyl ether, rendered basic to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The ether extract is evaporated, the residue dissolved in acetone and 0.4 ml of 8 N ethanolic hydrochloric acid are added, to yield the 1-(2-isopropylaminopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepine dihydrochloride melting at 257°-260° with decomposition.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][N:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Nc1ccc(F)cn1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F

Procedure:
3-Cyano-4-fluorobenzenesulfonyl chloride (5 g, 20 mmol), 5-fluoropyridin-2-amine (3.37 g, 30 mmol) and pyridine (4.87 mL, 60 mmol) in dichloromethane (100 mL) were stirred at room temperature for 2 hours before concentrating in vacuo. The residue was triturated in hydrochloric acid (2 N aqueous solution, 100 mL) for 16 hours. The precipitate was filtered to afford the title compound as a pale pink solid, 6.1 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.[O:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12]([N:27]1[CH2:28][CH2:29][C:24]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:25][CH2:26]1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCC2(CC1)OCCO2)C(=O)OC(C)(C)C

Procedure:
2-Chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester, dichloromethane (60 ml), triethylamine (82 ml), and 1,4-dioxa-8-aza-spiro[4.5]decane(1.59 g) were reacted as above. Purification by flash chromatography (eluent 50% hexane/diethyl ether) yielded the title compound as a green gum (1.57 g). Rf 0.35 (50% hexane/diethyl ether).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([NH:11][C:19](=[O:20])[O:21][CH3:22])[CH3:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(N)Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NC(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromophenyl)propan-2-amine (0.5 g, 2 mmol) in methylene chloride (5 mL) was added pyridine (380 uL, 4.7 mmol) and methyl chloroformate (270 uL, 3.5 mmol, Aldrich, Cat. No. M35304). The reaction mixture was stirred at r.t. overnight, and concentrated under reduced pressure. The residue was dissolved in EtOAc, and washed with NaHCO3 aqueous solution, 1N HCl aqueous solution and brine. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatograph on a silica gel column using 25% Ethyl acetate in hexane to afford the desired compound. LCMS (M+H)+: m/z=272.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>[Cl-].[Zn+2].[Cl-].Cl>[NH2:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][C:17]=1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(F)cc1F
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 9.5 %

Procedure:
A mixture of 2,4-difluorobenzoyl chloride (88.3 g) and 4-nitroaniline (32.9 g) was heated at 180° C. for 25 minutes. Zinc chloride (39 g) was added portionwise to the resulting mixture. The mixture was stirred for 2.5 hours at 195° C. and cooled to 130° C. To the mixture was added 3N hydrochloric acid (100 ml) and the resulting mixture was refluxed for 2 hours, then the supernatant was decanted out. 75% Sulfuric acid was added to the residue and the mixture was stirred at 130° C. for 2 hours. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was washed with 3N hydrochloric acid (600 ml), 3N sodium hydroxide (1 l), and water successively, dried, and evaporated. The solid residue (15 g) was recrystallized from ethanol to give crystals of 2-amino-5-nitro-2',4'-difluorobenzophenone (6.3 g).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][NH2:33].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][NH:33][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: NCCc1ccccc1Cl
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccccc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-varboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2-chloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H28Cl4NO5 [M−H]−: 434.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36]1[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=1>CS(C)=O.C(OCC)(=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36]1[CH2:37][CH2:38][N:39]([CH2:12][CH:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)[CH2:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]ccc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6[nH]ccc6c5O4)CC3)c2c1

Procedure:
A solution of 0.30 g (0.84 mmole) of (2R)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl 4-methylbenzenesulfonate and 0.40 g (1.8 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 30 mL of DMSO was heated at 65° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-1.5% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.10 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 112° C., with one-quarter mole of ether.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+].O>[C:16]1([C:15]([NH:1][CH:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=3)[CH2:3]2)=[O:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCc2ccc([N+](=O)[O-])cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCc2ccc([N+](=O)[O-])cc2C1)c1ccccc1

Procedure:
To 2-amino-7-nitrotetralin (1.8 g, 9.39 mmol, derived from dibenzoyl-L-tartaric acid) in THF (50 ml) and 10% K2CO3 (100 ml) was added benzoyl chloride (1.2 ml, 10.1 mmol). After the addition was complete, the mixture was diluted with water to a volume of 250 ml. The precipitated solids were collected by filtration, washed with water and dried in vacuo: (2.8 g, 100%), m.p. 208°-209° C., [α]D -24.0° (c 0.87 DMSO).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH3:18])[CH2:10][C:11](OC(C)(C)C)=[O:12].[BH4-].[Li+].CO>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:10][CH2:11][OH:12])[CH3:18]
Reactant: CC(C)(C)OC(=O)CC(C)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(CCO)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(2,3-difluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate (17.9 g, 47.7 mmol) in THF (250 mL) at ambient temperature was added lithium borohydride, 2m solution in THF (47.7 mL, 95 mmol) followed by MeOH (12 mL, slightly exothermic reaction. added slowly via syringe). After stirred for 2 h, the reaction was carefully quenched by the addition of saturated ammonium chloride, followed by water and EtOAc. The separated organic phase was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and dried in vacuum to afford (R)-N-(2-(2,3-difluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide as light yellow foam. It was carried to next step without purification. MS m/z=306.1 [M+H]+. Calculated for C14H21F2NO2S: 305.4
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:26])=[C:18]([CH2:20][NH:21][C:22](=[O:25])[CH2:23][Cl:24])[CH:19]=1)(OC(C)(C)C)=O.Cl.Cl.CCOCC>CO>[ClH:24].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:26])=[C:18]([CH2:20][NH:21][C:22](=[O:25])[CH2:23][Cl:24])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)CCl)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(CCl)NCc1cc(OC[C@@H]2CCN2)cnc1Cl
Yield: 37 %

Procedure:
The product of step 211a (0.34 g, 0.80 mmol) was deprotected and isolated as the free base in 37% yield according to the procedure of Example 20b, followed by conversion to the monohydrochloride with HCl/Et2O: [α]D23 +16.82 (c 0.3, MeOH); 1H NMR (D2O, 300 MHz) δ 2.72 (q, J=8.5, 16.5 Hz, 2H), 4.07-4.43 (m, 4H), 4.45 (s, 2H), 4.48 (d, J=4.5 Hz, 2H), 4.81 (m, 1H), 7.53 (d, J=3.0 Hz, 1H), 8.08 (d, J=3.0 Hz, 1 H); MS (CI/NH3) m/z 304 (M+H)+. Anal. Calcd for C12H15Cl2N3O2.HCl: C, 42.31; H, 4.73; N, 12.33. Found: C, 42.34; H, 5.00; N, 12.25.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:23]([C:27]1[CH:33]=[CH:32][C:30](N)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1[N+]([O-])=O)([O-])=O>COCCO>[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=4)[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Solvent: COCCO
Product: CC(C)(C)c1ccc(Nc2cccc3c2C(=O)c2ccc([N+](=O)[O-])cc2C3=O)cc1

Procedure:
The product employed in a) can be obtained as follows: 15 g of 1,6-dinitro-anthraquinone and 30 ml of p-tert.-butylaniline are stirred at 125° C until no further dinitro-anthraquinone is detectable (approx. 6 hours being required). The warm mixture is diluted with 30 ml of ethylene glycol monomethyl ether, stirred until cold and filtered, and the residue is successively washed with ethylene glycol monomethyl ether and water. 13.9 g of 1-(p-tert.-butyl-anilino)-6-nitro-anthraquinone are obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:13]([CH2:55][CH3:56])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]2[CH:34]=[CH:33][CH:32]=[C:24]([C:25]([N:27]([CH2:29][CH2:30][OH:31])[CH3:28])=[O:26])[CH:23]=2)=[C:16]([C:36]2[CH:41]=[C:40]([C:42](=[O:54])[NH:43][C@@H:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH2:47][CH2:46][CH2:45]3)[CH:39]=[CH:38][N:37]=2)[CH:15]=1)[CH3:12]>C(Cl)Cl>[CH2:55]([N:13]([CH2:11][CH3:12])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]2[CH:34]=[CH:33][CH:32]=[C:24]([C:25]([N:27]([CH3:28])[CH2:29][CH:30]=[O:31])=[O:26])[CH:23]=2)=[C:16]([C:36]2[CH:41]=[C:40]([C:42](=[O:54])[NH:43][C@@H:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH2:47][CH2:46][CH2:45]3)[CH:39]=[CH:38][N:37]=2)[CH:15]=1)[CH3:56]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCO)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CC=O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of DMSO (4.8 mmol, 375 mg) in DCM (3 mL) at −78° C. was added a solution of oxalyl chloride (2.4 mmol, 305 mg) in DCM (0.4 mL). The mixture was stirred at −78° C. for 15 minutes. Then a solution of (S)—N1-(4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)-N3-(2-hydroxyethyl)-N3-methylisophthalamide Example 194 (1.2 mmol, 742 mg) in DCM (1.7 mL) was added dropwise. The mixture was stirred at −78° C. for 3 h and quenched with triethylamine (0.85 mL). The mixture was stirred at −78° C. for 10 minutes, at 0° C. for 10 minutes, then diluted with water, and extracted with DCM (2×). The combined organic layers was washed with water (1×), dried, and concentrated. The residue was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=O.[NH2:16][NH2:17]>C(O)C>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[N:6][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:14]2
Reactant: COC(=O)c1cc2cc(F)ccc2cn1
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1cc2cc(F)ccc2cn1
Yield: 84.4 %

Procedure:
A solution of 6-fluoro-isoquinoline-3-carboxylic acid methyl ester (27 g) and hydrazine (42 g, 10 equiv.) in ethanol (500 mL) was refluxed for 2 h. The reaction mixture was concentrated under high vacuum to remove hydrazine, and the resulting residue was triturated with ethanol (100 mL) to give 6-fluoro-isoquinoline-3-carboxylic acid hydrazide as a light yellow solid (22.8 g, 84%). LRMS (M+H+) m/z 206.1.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A solution of (S)-(−)-1-Boc-2-pyrrolidine methanol (0.267 g, 1.33 mmol), phenol (0.38 g, 4.02 mmol) and triphenylphosphine (0.71 g, 2.71 mmol) in DCM (5 mL) was cooled in an ice-bath and a solution of diisopropyl azodicarboxylate (0.55 g, 2.71 mmol) in toluene (3 mL) was added. The ice-bath was removed and the reaction mixture was stirred at room temperature over the weekend. The mixture was diluted with ether and washed with sodium hydroxide (3 M), then brine, dried over sodium sulfate and evaporated. The resultant solid was suspended in ethyl acetate and cyclohexane and the resultant white crystalline solid was removed by filtration. The filtrate was evaporated and the crude material was purified by column chromatography using a 10 g Si II cartridge eluting with 10% ethyl acetate in cyclohexane to afford (S)-2-phenoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil (0.22 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:17]1[S:21][N:20]=[C:19]([CH3:22])[N:18]=1>CCO>[CH3:22][C:19]1[N:18]=[C:17]([N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)[S:21][N:20]=1
Reactant: O=C1CCNCC1
Reactant: Cc1nsc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nsc(N2CCC(=O)CC2)n1
Yield: 8.6 %

Procedure:
To a mixture of piperidin-4-one HCl salt (4.08 g, 30 mmol) and Et3N (20 mL, 78.6 mmol) in EtOH (50 mL) was added 5-chloro-3-methyl-1,2,4-thiadiazole (4.05 g, 30 mmol). The mixture was heated to reflux for 1.5 hours and then concentrated to dryness. The residue was dissolved in EtOAc. The solution was washed with water (30 mL×3) and brine (30 mL), dried over Na2SO4, and concentrated to dryness. The residue was recrystalled from ether to give 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (510 mg, 8.6%). 1H-NMR (300 MHz, CDCl3) δ 3.86 (t, J=6.3 Hz, 4H), 2.62 (t, J=6.3, Hz, 4H), 2.44 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cc(F)c(F)cc21
Reactant: C1CCNCC1
Solvent: c1ccncc1
Product: O=C1CCc2cc(N3CCCCC3)c(F)cc21

Procedure:
5,6-difluoro-indan-1-one (2.49 g, 14.8 mmol) and piperidine (4.4 ml, 3.78 g, 44.4 mmol) were dissolved in pyridine (10 ml) and heated to reflux for 16 hours. The reaction was cooled, and the solvent removed under vacuum. The residue was taken in ethyl ether, washed with 1N aqueous sodium hydroxide and water, dried with magnesium sulfate, and the solvent removed under vacuum to give the desired product as 2.97 g of a black solid that was used without further purification. 1H NMR (300 MHz, CDCl3) 7.32 (d, 1H), 6.88 (d, 1H), 3.19 (m, 4H), 3.03 (m, 2H), 2.66 (m, 2H), 1.73 (m, 4H), 1.62 (m, 2H). MS (CSI) m/e 234 (M+H)+
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([Cl:14])=[O:4]
Reactant: CCCCCCC(Br)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCC(Br)C(=O)Cl
Yield: 63.5 %

Procedure:
To a solution of 20 g (90 mmol) 2-bromooctanoic acid in 100 mL toluene was added 13.2 mL (180 mmol) thionyl chloride. The solution was heated at reflux under nitrogen for 3 hours. The excess thionyl chloride and toluene were distilled at atmospheric pressure under N2. The yellow residue was purified by kugelrohr distillation (bp=60°-65° C./0.1 mm Hg) and 13.8 g (64%) of the 2-bromooctanoyl chloride as a colorless oil was isolated.