Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@@H:7]([OH:21])[CH2:8][NH:9][C@H:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][C@H:10]([N:9]1[CH2:8][C@@H:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)NC[C@H](O)COc1cccc(Cl)c1
Reactant: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)N1C[C@@H](COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 0.92 g of 1(S)-(3-chlorophenoxymethyl)-2-[2-t-butyldimethylsilyloxy-1(R)-methylethylamino]ethanol (prepared as described in Preparation 26), 0.48 g of N,N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide were used, to give 0.92 g of the title compound having an Rf value of 0.25 (on silica gel thin layer chromatography, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =+34.1° (methanol, c=0.960).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([S:11]CC2C=CC(OC)=CC=2)[CH:8]=[C:7]([F:21])[CH:6]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([F:21])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(SCc2ccc(OC)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(F)cc(S)c1
Temperature: 25 °C

Procedure:
3-Fluoro-5-(4-methoxy-benzylsulfanyl)-benzoic acid ethyl ester (7.24 g, 22.5 mmol)was stirred in TFA (10 mL) at 70° C. for overnight. The resulting mixture was cooled to room temperature and subjected to standard aqueous workup. The crude residue was purified on silica gel (0-30% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])=[N:5][N:6]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[CH:7]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[C:4]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:27])([F:28])[F:29])=[N:5][N:6]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:41])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[CH:7]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2cc(C#N)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2cc(C#N)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 92 %

Procedure:
0.2 g of 4-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 93 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.19 g of 4-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [C:1]1([C:7]2([C:13](=[O:16])[CH2:14][CH3:15])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[C:1]1([C:7]2([C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:9][N:10]([CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: CCC(=O)C1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCC(=O)C1(c2ccccc2)CCN(CCCc2ccccc2)CC1

Procedure:
6 g 4-phenyl-4-propionylpiperidine and 3.6 ml 1-bromo-3-phenylpropane was refluxed in 500 ml n-butanol with 10 g sodium carbonate for 16 hours. The reaction mixture was filtered through a silica plug and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, then saturated brine and dried over potassium carbonate. The solution was concentrated in vacuo, 8 g of the residue was taken up in 150 ml acetonitrile and heated with 2.5 g fumaric acid. The resulting precipitate was collected by filtration, giving 3 g 4-phenyl-1-(3-phenylpropyl)-4-propionylpiperidine as the fumarate salt, melting point 136°-138° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(NCCCCNS(C)(=O)=O)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 99 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (21 mg, 0.04 mmol) in dichloromethane (3 mL) was added triethylamine (0.02 mL, 0.13 mmol) and methanesulfonyl chloride (0.05 mL). The resultant solution was stirred at 0° C. for 1 hour and saturated aqueous sodium bicarbonate was added. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) provided N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)methanesulfonamide (25 mg, 99%) a yellow solid. 1H NMR (CDCl3): δ 8.01 (d, 1 H), 7.79 (d, 1 H), 7.59 (d, 2 H), 7.32 (m, 1 H), 7.01 (d, 2 H), 6.34 (d, 1 H), 6.13 (m, 1 H), 6.00 (d, 1 H), 5.34 (d, 1 H), 5.02 (m, 1 H), 4.38 (m, 1 H), 3.90 (s, 3 H), 3.38 (m, 2 H), 3.13 (m, 2 H), 2.94 (s, 3 H), 2.14–2.06 (m, 2 H), 1.82–1.54 (m, 10 H); MS m/z 550 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[F:11])=[O:3].[BH4-].[Na+].[OH-].[Na+].Cl>C(O)(C)C.O>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([F:11])[C:4]=1[CH:2]([OH:3])[CH3:1]
Reactant: CC(=O)c1c(F)cccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(O)c1c(F)cccc1F
Reaction time: 1 h

Procedure:
2,6-Difluoroacetophenone of (A) (17.2 g, 0.11 mol) is dissolved in isopropyl alcohol (50 ml) and NaBH4 (2.0 g, 0.055 mol) is added. The resultant mixture is warmed to 60° C. for about 14 hours. A solution of NaOH (4.9 g, 0.12 mol) in water (20 ml) is then added. After 1 hour at 60° C., this reaction mixture is cooled and acidified with dilute HCl. Extraction with methylene chloride provided pure title product (14.9 g, 85.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][C@@H:26]2[O:29][CH:30]=[O:31])[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@H:19]([O:32][CH:33]=[O:34])[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][C@@H:26]2[O:29][CH:30]=[O:31])[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@H:19]([O:32][CH:33]=[O:34])[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9]
Reactant: COC(=O)/C=C/CCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3C[C@H](OC=O)[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3C[C@H](OC=O)[C@]12C
Yield: 98.3 %

Procedure:
A mixture of 1 g of 10% Pd/C and 7.6 g of 5-(3α,12α-diformyloxy-5β-pregnane-20-yl)-trans-2-pentenoic acid methyl ester in 100 ml of ethyl acetate was hydrogenated at atmospheric pressure. After completion of the reaction, the catalyst was filtered and the solvent removed under reduced pressure. Trituration of the residue with ether-hexane afforded 7.5 g of 5-(3α,12α-diformyloxy-5β-pregnane-20-yl)-pentanoic acid methyl ester mp 67-72°.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.C([CH:15]([C:23]([NH2:25])=[O:24])[CH:16](CC=C)[C:17]([NH2:19])=[O:18])C=C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]([CH:15]([C:23]([NH2:25])=[O:24])[CH2:16][C:17]([NH2:19])=[O:18])=[N:2]1
Reactant: C1=Cc2ccccc2NN=C1
Reactant: C=CCC(C(N)=O)C(CC=C)C(N)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC(C(N)=O)C1=NNc2ccccc2C=C1

Procedure:
Following the procedures described for the synthesis of 11, diallylsuccinamide intermediate 16 was prepared from 14 in reasonable yield. 14 (2.5 g, 5.9 mmol), p-chloro-BZD (2.34 g, 6.2 mmol) and DIPEA (1 ml, 5.8 mmol) in 30 ml DMF was heated to 40-50 degree overnight.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[CH3:11][S:12][C:13](=[N:16][C:17]#[N:18])SC>>[C:17]([NH:16][C:13](=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[S:12][CH3:11])#[N:18]
Reactant: NCCCCc1c[nH]cn1
Reactant: CSC(=NC#N)SC
Product: CSC(=NCCCCc1c[nH]cn1)NC#N

Procedure:
Reaction of 4-(4-aminobutyl)imidazole with dimethylcyanodithioimidocarbonate gives N-cyano-N'-[4-(4-imidazolyl)butyl]-S-methylisothiourea which when reacted by the procedure of Example 12 with the following compounds:
Reaction SMILES: C(C(C)=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][Cl:47]>O>[Cl:47][CH2:46][CH2:45][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:32][CH:33]=2)[CH3:27])=[CH:9][CH:8]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCl)cc2)cc1
Yield: 47.8 %

Procedure:
To methyl ethyl ketone solution (3 ml) of (3RS,4RS)-4-(4-hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-thiochroman (126 mg, 0.28 mmol) were added potassium carbonate (96 mg, 0.70 mmol) and 1-bromo-2-chloroethane (115 ml, 1.38 mmol), and the mixture was heated under refluxing for 70 hours. After adding water, the reaction solution was extracted with ethyl acetate. The extract was distilled under reduced pressure to remove the solvent and the crude product thus obtained was then purified using silica gel plate (ethyl acetate:hexane=1:2) to obtain 69 mg (yield: 48%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>>[C:15]([O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12)(=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(NCCO)c2[nH]ncc2n1
Product: CCC(=O)OCCNc1cc(C)nc2cn[nH]c12

Procedure:
The title compound was prepared from 7-(2-hydroxyethylamino)-5-methyl-1H-pyrazolo[4,3-b]pyridine (2 g) and propionyl chloride by the method of Example 4. After purification by column chromatography on basic alumina with ethyl acetate and then a rising percentage of methanol as eluant the title compound was obtained as a white solid (1.7 g, 66%), m.p. 187°-190° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C(=O)N([Br:31])C(=O)C1.C1C(=O)N(Br)C(=O)C1.C1COCC1>C1COCC1>[Br:31][CH:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4]1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(c1)OCCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)OCC(Br)C2=O
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 62.5 %

Procedure:
4-Oxochroman-7-carbonitrile (11.0 g, 63.5 mmol) was dissolved in THF (250 mL) and cooled to −30° C. prior to the addition of LiHMDS (66.7 mL, 66.7 mmol) dropwise. The resulting solution was stirred for 20 min. Next, the temperature was lowered to −78° C. and the solution was stirred for 0.5 h. In another flask, NBS (11.3 g, 63.5 mmol) was dissolved in THF (250 mL) and cooled to −78° C. Then the anion solution was transferred into NBS/THF solution at −78° C. via cannula. The resulting solution was stirred at −78° C. for 40 min. The reaction was quenched with aqueous saturated NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with 1N HCl, brine, dried (MgSO4), and filtered. The filtrate was concentrated and the resulting residue was purified by flash chromatography with 10% to 20% EtOAc/hexane on 120 g ISCO column to afford 3-bromo-4-oxochroman-7-carbonitrile (10.0 g, 39.7 mmol, 62.5% yield) as a pale yellow solid: LCMS=251.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)o1

Procedure:
4-Fluoro-phenylboronic acid (611 mg, 4.4 mmol) was coupled to 5-bromo-2-furoic acid (1 g, 5.2 mmol) using Method F to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>>[F:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([NH:29][CH2:16][C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)[CH2:27][CH2:28]1
Reactant: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Reactant: CCc1cc(-c2ccc(C=O)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(CNC3CCN(Cc4cc(F)cc(F)c4)CC3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]thiophen-2-carbaldehyde is reacted with 1-(3,5-difluoro-benzyl)-piperidin-4-ylamine as described in Method A of Example 123 to give the title compound. MS: m/e 458 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH-].[Na+].[NH2:9][CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14]>>[CH2:5]([O:4][C:2]([NH:9][CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)NCC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Ethyl chloroformate (3.19 g, 29.4 mmol) was added to a 2N sodium hydroxide solution (26.3 ml, 52.4 mmol) of 4-amino-3-(3,4-dichlorophenyl)butyric acid (5.61 g, 22.6 mmol) under cooling with ice water and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. The reaction solution was washed with diethyl ether and the aqueous layer was adjusted to a pH of about 2 with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (7.23 g, quant.) as a light brown oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:32]([CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[CH3:33])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1cc(C(=O)Cl)ccc1CCc1cnc2c(N)nc3ccccc3c2c1
Reactant: CNCCN(C)C
Product: Cc1cc(C(=O)N(C)CCN(C)C)ccc1CCc1cnc2c(N)nc3ccccc3c2c1

Procedure:
4-(2-(5-Aminobenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-(dimethylamino)ethyl)-N,3-dimethylbenzamide was prepared from 4-(2-(5-aminobenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and N1,N1,N2-trimethylethane-1,2-diamine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.84 (s, 1H), 8.63 (s, 1H), 8.39 (d, 1H), 7.76-7.83 (m, 2H), 7.60-7.64 (m, 1H), 7.37 (s, 1H), 7.19-7.29 (m, 2H), 3.96 (t, 2H), 3.48 (t, 2H), 3.32 (t, 2H), 3.20 (t, 2H), 3.09 (s, 3H), 3.06 (s, 6H), 2.42 (s, 3H). LRMS [M+H]=442.3
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:15][CH2:16][OH:17].[OH-].[K+].C(O)(=O)C>O>[CH3:1][O:2]/[N:3]=[C:4](/[C:5]1[O:17][CH2:16][CH2:15][O:14][N:13]=1)\[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6]
Reactant: CON=C1C(=NOCCO)Oc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CO/N=C(/C1=NOCCO1)c1ccccc1O
Temperature: 10 °C
Yield: 69.1 %

Procedure:
A solution of 25.6 g (0.1084 mol) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime]3-(O-methyl-oxime) and 14.2 g (0.216 mol) of potassium hydroxide pellets in 250 ml of water is stirred at 60° C. for 195 minutes. The solution is cooled to 10° C. and acidified to pH 5-6 with glacial acetic acid. The crystalline product is filtered off with suction, washed with 200 ml of water a little at a time and dried at 45° C. in a vacuum drying oven. 17.7 g (67.7% of theory) of E-(5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:22])[CH2:29][O:28][CH2:27]1
Reactant: CC1(N)COC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 90 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 3-methyl-3-oxetanamine instead of 2-amino-2-methyl-1-propanol, to the title compound (109 mg, 90%), which was obtained as a white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)/[C:4]([O:6]CC)=O)#[N:2].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCC>[OH:6][C:4]1[C:12]2[C:11](=[CH:16][CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=2)[N:10]=[CH:9][C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)/C(C#N)=C/Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1O
Temperature: 50 °C
Yield: 60.7 %

Procedure:
A mixture of (E)-ethyl 2-cyano-3-((4-nitrophenyl)amino)acrylate (24.0 g) and Dowtherm A (500 mL) was added to a 1 L flask, the mixture was heated to reflux under nitrogen for 10 hours. After cooling to 50° C., the mixture was diluted with hexane (1 L). The product was filtered, washed with ethanol (100×2 mL), and dried to give 4-hydroxy-6-nitroquinoline-3-carbonitrile (Compound 16) as a brown solid (12.0 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[OH:25])=[C:11]([C:40]3[CH2:41][CH2:42][O:37][CH2:38][CH:39]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-(trifluoromethyl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C@H:8]([OH:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C:18]1[CH:17]=[CH:16][C:15]([OH:22])=[CH:14][C:13]=1[CH2:12][CH2:11]3.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27]>ClCCl.CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27].[CH3:1][N:2]([CH3:23])[C@H:3]1[C@H:8]([OH:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C:18]1[CH:17]=[CH:16][C:15]([OH:22])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CN(C)[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C

Procedure:
17β-Methylamino-oestra-1,3,5(10)-triene-3,16α-diol (1.7 g) was dissolved in dichloromethane (17 ml) and a solution of maleic acid (0.63 g) in methanol (6.3 ml) was added. The resulting solution was evaporated to low volume and acetone was added to give pure 17β-dimethylamino-oestra-1,3,5(10)-triene-3,16α-diol (Z)-2-butenedioate (1:1) (salt) as prisms (1.76 g; 75.5%), m.p. 188°-194° C., [α]D +36.1° (c 0.98 in MeOH).
Reaction SMILES: CO[C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)[F:5].[C-:30]#[N:31].[Na+]>CN>[C:23]1([S:20]([C:4]([CH:6]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=4)[NH:9][C:8]=3[CH2:7]2)([F:5])[C:3]([NH:31][CH3:30])=[O:29])(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [C-]#N
Reactant: COC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: CN
Agent: [Na+]
Product: CNC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 289.5 %

Procedure:
To 400 mg (0.92 mmol) of (RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester (from example 12) in a sealed tube were added 20 mL of methylamine (33% wt. solution in EtOH) and 13 mg (0.27 mmol, 0.3 eq) of sodium cyanide. The reaction mixture was stirred at 90° C. for 2 hours, and the solvent was evaporated. Column chromatography on silica gel with EtOAc yielded 340 mg (86%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide as a white solid, MS: 435 (MH+).