Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1.[Br:50][C:51]1[CH:52]=[C:53]2[C:58](=[C:59](O)[CH:60]=1)[N:57]=[C:56]([Cl:62])[N:55]=[CH:54]2>C1COCC1.CO>[Br:50][C:51]1[CH:52]=[C:53]2[C:58](=[C:59]([O:36][CH:37]3[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]3)[CH:60]=1)[N:57]=[C:56]([Cl:62])[N:55]=[CH:54]2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cc(Br)cc2cnc(Cl)nc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc3cnc(Cl)nc23)CC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (577 mg, 2.20 mmol), di-tert-butylazodicarboxylate (506 mg, 2.20 mmol) and tert-butyl 4-hydroxy-piperidine-1-carboxylate (1.32 g, 6.62 mmol) are taken up in 6 mL THF, stirred for 15 min at 20° C. and then combined with 6-bromo-2-chloro-quinazolin-8-ol (1.16 g, 4.45 mmol). After stirring for 24 h at 20° C. the mixture is diluted with MeOH, the solvent is eliminated in vacuo, the crude product is purified by RP-chromatography (method prep. HPLC1; 20% acetonitrile to 90% in 6 min) and tert-butyl 4-(6-bromo-2-chloro-quinazolin-8-yloxy)-piperidine-1-carboxylate (HPLC-MS: tRet.=1.99 min; method FECB5) is obtained.
Reaction SMILES: [OH-].[Na+].[N+:3]([CH:6]=[CH:7][NH:8][C:9]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)([O-:5])=[O:4].CO>O>[N+:3]([C:6]1[CH:7]=[N:8][C:9]2[C:10]([C:11]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)([O-:5])=[O:4]
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1NC=C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cnc2ccc(C(F)(F)F)cc2c1-c1ccccc1
Yield: 85.9 %

Procedure:
2N-Sodium hydroxide solution (9.0 ml) was added dropwise to a mixture of 2-(2-nitrovinylamino)-5-trifluoromethylbenzophenone (6.0 g) and methanol (60 ml) under stirring. After stirring further for 30 mins. at room temperature, the mixture was diluted with water to give 3-nitro-4-phenyl-6-trifluoromethylquinoline as crystals (4.88 g, 4.5 %). It was recrystallized from a mixture of chloroform and methanol to give pale yellow needles (4.50 g, 79,2 %). m.p 192°-193° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18](O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>>[CH3:18][N:12]1[CH2:17][CH2:16][N:15]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:14][CH2:13]1
Reactant: CC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
p-Nitrobenzaldehyde (2.50 g, 16.5 mmol) and piperazine, 1-methyl- (3.31 g, 33.1 mmol) were dissolved in Acetic acid (2.0 mL, 35 mmol) and Methylene chloride (100 mL, 2000 mmol) and the solution was allowed to stir at room temperature for approximately 15 minutes. Sodium triacetoxyborohydride (5.26 g, 24.8 mmol) was then added and the reaction was allowed to stir overnight. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent). Combined fractions were reduced and dried under vacuum to afford 3.77 g of 1-Methyl-4-(4-nitro-benzyl)-piperazine. (M+H)=236.6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.[CH:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O.[C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[N:28].N1CCCCC1>C(O)C>[NH2:28][C:27]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:9]([CH3:16])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)/C=C(\C)Nc1cccc(C)c1
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(C)N(c2cccc(C)c2)C(N)=C(C(=O)OCC)C1c1ccc(C#N)cc1

Procedure:
Under argon, 100 mg (0.46 mmol) ethyl(2E)-3-[(3-methylphenyl)amino]-2-butenoate (preparation analogously to Example 1A), 59.80 mg (0.46 mmol) 4-formylbenzonitrile and 51.58 mg (0.46 mmol) ethyl cyanoacetate are dissolved in 2 ml ethanol. 77.66 mg (90 μl, 0.91 mmol) piperidine are added to the mixture which is stirred at reflux overnight. After the reaction is finished, the mixture is purified by preparative HPLC followed by column chromatography on silica with dichloromethane as eluent.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:1]1[C:6]2[CH2:7][N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Reactant: CCOC(=O)CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN1Cc2ccccc2Oc2ccccc21
Temperature: 70 °C
Reaction time: 60 h
Yield: 36.9 %

Procedure:
Title compound 398 (0.304 g, 1.54 mmol) was dissolved in acetonitrile (5.0 mL) and the ethyl 7-iodoheptanoate (0.613 g, 2.16 mmol) and the potassium carbonate (0.639 g, 4.62 mmol) were added. The reaction mixture was stirred at 70° C. for 60 hours. The mixture was cooled down and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography with 10% ethyl acetate in hexanes to afford title compound 399 (201 mg, 37%). MS (m/z): 354.2 (M+H).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH3:54][O:55][CH2:56][CH2:57][S:58]([NH2:61])(=[O:60])=[O:59]>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:42][CH2:43][C:44]([F:47])([F:48])[CH2:45][CH2:46]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:61][S:58]([CH2:57][CH2:56][O:55][CH3:54])(=[O:60])=[O:59])=[O:36])[CH2:27][CH2:28]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with 2-methoxyethanesulfonamide, the title compound was obtained (0.072 g, 26%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.70-8.58 (m, 1H), 7.63-7.53 (m, 1H), 6.63-6.51 (m, 1H), 3.93-3.83 (m, 4H), 3.83-3.75 (m, 2H), 3.31 (s, 3H), 2.27-2.09 (m, 2H), 2.08-1.66 (m, 6H), 1.61-1.42 (m, 2H), 0.99-0.88 (m, 2H), 0.71-0.60 (m, 2H); MS (ES+) m/z 450.0 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH3:9].[CH3:21][N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=O.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O>C(#N)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]([CH2:8][CH3:9])[C:24]([C@@H:23]2[CH2:27][CH2:28][CH2:29][N:22]2[CH3:21])=[O:26])=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: CCNc1ccc(N)c([N+](=O)[O-])c1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(C(=O)[C@@H]1CCCN1C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
Triethylamine (1.0 mL, 7.33 mmol) was added to a stirred solution of N1-ethyl-3-nitrobenzene-1,4-diamine (440 mg, 2.43 mmol), N-methyl-L-proline (314 mg, 2.43 mmol) and DEPBT (727 mg, 2.43 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature and further aliquots of N-methyl-L-proline (314 mg, 2.43 mmol), DEPBT (727 mg, 2.43 mmol), and triethylamine (1.0 mL, 7.33 mmol) were added after 1, 2, and 3 days. After stirring for a further 1 day, the mixture was concentrated and the residue taken up in EA (75 mL). The EA solution was extracted with water, and with 1M sodium carbonate solution (2×). The combined water and 1M sodium carbonate solution extracts were back-extracted with EA (4×) and the combined EA extracts washed with brine, dried over magnesium sulfate, and concentrated to give (S)—N-(4-amino-3-nitrophenyl)-N-ethyl-1-methyl-pyrrolidine-2-carboxamide (388 mg) as an orange/brown oil. This was hydrogenated in ethanol, using 10% palladium on carbon (153 mg) as the catalyst. After stirring overnight under a hydrogen atmosphere (balloon), the mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated to give (S)—N-(3,4-diaminophenyl)-N-ethyl-1-methylpyrrolidine-2-carboxamide (335 mg).
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[C:6]([CH3:13])[CH:5]=[CH:4][N:3]=1.[NH3:14]>>[CH3:13][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:14])[C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: Cc1ccnc(F)c1-n1cccc1
Reactant: N
Product: Cc1ccnc(N)c1-n1cccc1
Temperature: 150 °C
Yield: 76 %

Procedure:
2-Fluoro-4-methyl-3-(1H-pyrrol-1-yl)pyridine (3.9 g, 22.1 mmol) was dissolved in 80 mL of ammonia solution (7N in MeOH) in a sealed tube (350 mL). The mixture was heated at 150° C. for 2 days protected with a blast shield. The mixture was cooled to room temperature, then cooled in the ice for minutes. The filtrate was evaporated to dryness and purified by flash chromatography (EtOAc/Hexanes=1:1, Rf=0.5) to give 2.9 g (76%) white solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=5.1 Hz, 1H) 6.67 (t, J=2.1 Hz, 2H), 6.60 (d, J=5.2 Hz, 1H), 6.41 (t, J=2.1 Hz, 2H), 4.52 (s, 2H), 2.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.1, 147.2, 145.9, 121.5, 121.1, 116.0, 110.0, 16.7. HRMS (m/z): calcd for C10H12N3 (M+H) 174.1031. found 174.1026. Peet & Sunder (1986) Heterocycles 24:3213-3221.
Reaction SMILES: C[O:2]C1C=C(NC(=O)C(O)=O)C=CC=1C1OC=NC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:33][C:34](=[O:46])[CH2:35][C:36](NC2C=CC=C(C)C=2)=[O:37])[CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:33][C:34](=[O:46])[CH2:35][C:36]([OH:37])=[O:2])[CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1
Reactant: COc1cc(NC(=O)C(=O)O)ccc1-c1cnco1
Reactant: COc1cc(NC(=O)CC(=O)Nc2cccc(C)c2)ccc1-c1cnco1
Product: COc1cc(NC(=O)CC(=O)O)ccc1-c1cnco1

Procedure:
56A was prepared from 55 by a route analogous to that used for the preparation of 5A. LC/MS: ret. timeA=2.611 min., MS (M+H)+=277. 56B. Preparation of N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methylphenyl) propanediamide
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:23](=[CH:24][CH:25]=1)[C@@H:22]1[C@H:13]([C@H:14]3[C@@:18]([CH2:20][CH2:21]1)([CH3:19])[C:17]([F:27])([F:26])[CH2:16][C@@H:15]3[CH2:28][CH2:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32])[CH2:12][CH2:11]2)=[O:7])CCC.[Li+].[OH-].CO>O>[N:33]1([C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C@@H:15]2[C@H:14]3[C@H:13]4[C@H:22]([CH2:21][CH2:20][C@:18]3([CH3:19])[C:17]([F:26])([F:27])[CH2:16]2)[C:23]2[C:10](=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:25][CH:24]=2)[CH2:11][CH2:12]4)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: CCCCOC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]3[C@@H](CCCC(=O)N4CCOCC4)CC(F)(F)[C@@]3(C)CC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1[C@@H](CCCC(=O)N1CCOCC1)CC2(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
796 mg 15α-(4-morpholin-4-yl-4-oxobutyl)-17,17-difluoro-estra-1(10),2,4-triene-3-carboxylic acid butyl ester and 5 eq LiOH are mixed with 30 ml MeOH and 10 ml H2O and stirred at 50° C. (water bath) for about 4 h. Then a few mg LiOH, 30 ml MeOH and 10 ml H2O were added and the reaction mixture was stirred for another 2 h at 50° C. After reducing the solvents, H2O is added, the reaction mixture is extracted with EtOAc. The combined aquatic layers are acidified with KHSO4aq to pH 2-3, and extracted twice with EtOAc. The latter organic layers are combined, washed with brine, dried (Na2SO4) and the solvent removed. Purifying by column chromatography (CH2Cl2: MeOH:AcOH 37:3:0.1) give 191 mg of pure 15α-(4-morpholin-4-yl-4-oxobutyl)-17,17-difluoro-estra-1(10),2,4-triene-3-carboxylic acid (=EXAMPLE 7, for NMR see below). 15α-(4-morpholin-4-yl-4-oxobutyl)-17,17-difluoro-estra-1(10),2,4-triene-3-carboxamide
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11](OC2C=CC=CC=2)[N:10]=1.[C:30]1([CH:37]=[CH:36][CH:35]=[C:33]([OH:34])[CH:32]=1)[OH:31].[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC.C1(C)C=CC=C(C)C=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:35]2[CH:36]=[CH:37][C:30]([OH:31])=[CH:32][C:33]=2[OH:34])[N:10]=1
Reactant: Cc1ccc(-c2nc(Oc3ccccc3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cccc(C)c1
Solvent: CCCCCCC
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a 250 mL round-bottomed flask fitted with a magnetic stirrer, a condenser and a nitrogen atmosphere are charged 7.85 g (0.0206 mol) of the product of Example 2, 13.5 g (0.123 mol) of resorcinol, 4 mL of m-xylene and 0.954 g (7.16 mmol) of aluminum chloride. The mixture is heated to 150° C. for 13.5 hours and then allowed to cool to 90° C. Portions of 2N hydrochloric acid and heptane are added and the mixture is stirred at 90° C. for 30 minutes followed by stirring for 18 hours at room temperature. The mixture is then warmed to 35° C. The crude solid formed is collected by vacuum filtration and is washed with portions of water and heptane. The solid is then recrystallized twice from methanol to afford 4.76 g (62% yield) of the title compound as a yellow solid melting at 194-196° C.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[N:18]1([CH2:24][CH2:25][C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[CH:28][N:27]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>ClCCCl>[N:18]1([CH2:24][CH2:25][C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[C:28]([C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:12])[N:27]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: c1ccn2c(CCN3CCOCC3)ncc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1cccc2ccccc12)c1nc(CCN2CCOCC2)n2ccccc12
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a solution of naphthoylchloride (0.28 mL, 1.85 mmol) in 1,2-dichloroethane (20 mL) was added aluminum trichloride (300 mg, 2.25 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine (200 mg, 0.87 mmol) in 1,2-dichloroethane (5 mL) was added. The mixture was stirred at ambient temperature for 30 min. then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (160 mg, 48%). 1H NMR (DMSO-d6 δ 8.56 (1H), 8.27 (1H), 8.07 (1H), 8.02 (2H), 7.76 (1H), 7.51 (4H), 7.11 (1H), 3.52 (4H), 3.18 (2H), 2.67 (2H), 2.40 (4H); m/z (M+H)=386.2.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>O1CCCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:31])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: O=C=Nc1ccccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccccc3Br)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-bromophenyl isocyanate (396 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 36 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to afford 10c as solid. Yield: 540 mg, 65.61%.
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[N:14]=[CH:13][C:12](N)=[CH:11][C:10]=1[CH3:16].[CH2:17]([OH:22])[C:18]([F:21])([F:20])[F:19].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:8][C:9]1[C:10]([CH3:16])=[CH:11][C:12]([O:22][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:13][N:14]=1
Reactant: Cc1cc(N)cnc1Cl
Reactant: OCC(F)(F)F
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC(F)(F)F)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Tert-butyl nitrite (1.60 g, 0.0156 mol, Sigma-Aldrich) was added drop wise to a stirred solution of 6-chloro-5-methylpyridine-3-amine (2.0 g, 0.0140 mol) in trifluoroethanol (10.05 g, 0.100 mol) and TFA (2.42 g, 0.0212 mol) at ambient temperature, followed by slow addition of potassium carbonate (4.40 g). The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2×300 mL). The combined organic layer were washed with brine, dried over sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography, eluting with 5% ethyl acetate in petroleum ether to give 2-chloro-3-methyl-5-(2,2,2-trifluoroethoxy)pyridine (1.30 g, 41.13% yield) as a reddish oil. MS m/z=225.02 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[C:28]2[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[CH:10]1C(=O)O[C:13](C)([CH3:17])[O:12][C:11]1=[O:19]>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[C:28]2[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[CH2:10][C:11]([O:12][CH2:13][CH3:17])=[O:19]
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1Cl)c1c[nH]c2c(CSC)cccc12

Procedure:
5.3 mg (0.08 mmol) of copper powder were added to 3.99 g (8.34 mmol) of the compound from Example 17A in 59 ml of pyridine and 15 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 2.34 g (67% of theory) of the title compound.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[C:16]1([CH:26]=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[CH3:28][N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:34]([C:30]3[N:29]([CH3:28])[CH:33]=[CH:32][CH:31]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: Cn1cccc1C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccn3C)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-naphthaldehyde, followed by 1-methyl-1H-pyrrole-2-carbaldehyde. Mass: 442.35 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I-:9].[K+].II>N.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: [I-]
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Product: Oc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of 4-bromophenol (25 g, 144.5 mmol) in 25% aqueous ammonia solution (350 mL) was added a solution of potassium iodide (72 g, 433.5 mmol) and iodine (36.7 g, 144.5 mmol) in water (288 mL). The reaction mixture was stirred at ambient temperature for 2 h and quenched with 250 mL of water. The reaction was acidified by addition of concentrated HCl (350 mL) and extracted with dichloromethane. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 9:1 hexanes/ethyl acetate) providing 4-bromo-2-iodophenol (33 g, 77%) as a pink solid: 1H NMR (CDCl3, 300 MHz) δ 7.78-7.75 (m, 1H), 7.37-7.31 (m, 1H), 6.88 (d, J=8.7 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[CH2:16]Br>>[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Clc1ccc(Cl)c(CBr)c1
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(Cl)ccc1Cl
Yield: 69 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.012 g) was reacted with 2,5-dichlorobenzyl bromide as in General Procedure 1 to give the title compound as a brown solid (69% yield). M.p.>200° C., LCMS: m/z=434.36 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.18 (2H, s), 5.07 (2H, s), 4.18 (2H, s), 7.14 (1H, d, J=1.8 Hz), 7.15 (1H, d, J=2.3 Hz), 7.40 (1H, dd, J=8.6, 2.5 Hz), 7.56 (1H, d, J=8.6 Hz), 7.85 (1H, d, J=1.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:36].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:36])=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC=C(CC)C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 74.3 %

Procedure:
In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1-hydroxycarbonyl-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 0.33 mmol) prepared in example 81c was reacted with cyanuric fluoride (0.044 mL, 1.64 mmol) (Alfa) and pyridine (0.13 g, 1.64 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.12 g, 75%).