Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:16]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: CCOC(=O)/C=C/c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 g (7.43 mmol) of ethyl (E)-3-(4-bromomethylphenyl)acrylate is added to a suspension of 0.69 mL (8.2 mmol) of pyrrolidine and 2.05 g (14.86 mmol) of potassium carbonate in 40 mL of DMF and stirred for 18 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted with water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated down, and the residue is purified by column chromatography on silica gel (eluant: dichloromethane/methanol/ammonia (90:10:1)). Yield: 0.3 g (15.6% of theory); C16H21NO2 (M=259.35); calc.: molecular ion peak (M+H)+: 260; found: molecular ion peak (M+H)+: 260; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:22]=1)[CH2:16][N:17]=[N+]=[N-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].ClCCl.[N-]=[N+]=[N-]>[Pd].CCOCC.CO>[CH2:24]([O:23][C:21]1[CH:20]=[C:15]([CH:14]=[C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:22]=1)[CH2:16][NH2:17])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCC)c1
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCOc1cc(CN)cc(OCCCCCCCCCCC)c1
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Catalytic (5% by mass) palladium on carbon (0.58 g) was placed into a hydrogenation bottle. The bottle was then placed under N2. To the bottle, 50/50 ether methanol (10 mL) was added. 3,5-diundecoxybenzyl azide (5.0 g, 11.2 mmol) was dissolved in 50/50 ether/methanol (60 mL) and transferred to the bottle. The bottle was attached to a hydrogenator with H2 pressure set at 40 psi and left for 1 hour. Thin layer chromatography (dichloromethane/10% hexanes) indicated that the azide was still present. As a result, the bottle was left on a hydrogenator with H2 pressure at 40 psi for an additional 30 minutes. Thin layer chromatography then showed that the starting material was completely consumed. The contents of the bottle were then vacuum filtered over celite. The filtrate was concentrated using rotary evaporation and then placed under high vacuum for 4 or more hours. This produced a 4.4 g yield or a 93.1% yield of the derivative. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.86 (t, J=6.3, 6H, CH2CH3), 1.25-1.45 (m, 32H, CH2(CH2)8), 1.74 (p, J=6.6, 4H, OCH2CH2), 3.76 (s, 4H, OCH2), 3.90 (t, J=6.6, 2H, ArCH2Cl), 6.32 (t, J=2.2, 1H, ArH), 6.43 (d, J=2.2, 2H, ArH). 13C NMR (75 MHZ, CDCl3): 14.20, 22.78, 26.14, 29.36, 29.42, 29.49, 29.67, 31.99, 46.35, 68.07, 99.86, 105.56, 144.47, 160.59.
Reaction SMILES: [N+](=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N-].[N+](=C)=[N-].[OH:16][CH:17]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:22]([NH2:24])=[O:23].OC(CCCCC)CCCN(CCCCCCC(O)=O)C(N)=S>CCOCC>[OH:16][CH:17]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:32])[C:22]([NH2:24])=[O:23]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=O
Reactant: CCCCCCCCCC=[N+]=[N-]
Agent: C=[N+]=[N-]
Agent: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=S
Solvent: CCOCC
Product: CCCCCCCCCCOC(=O)CCCCCCN(CCCC(O)CCCCC)C(N)=O

Procedure:
Using the method of Example 23 but substituting an ether solution of 1-diazodecane for the ether solution of diazomethane and 7-[1-(4-hydroxynonyl)ureido]heptanoic acid for 7-[1-(4-hydroxynonyl)thioureido]heptanoic acid, there is obtained decyl 7-[1-(4-hydroxynonyl)ureido]-heptanoate as a viscous oil.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>C1C=CC=CC=1>[C:12]([NH:11][C:10]1[CH:9]=[C:8]([CH:20]=[CH:19][CH:18]=1)[NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C1CC(=O)O1
Reactant: CCCCC(=O)Nc1cccc(N)c1
Solvent: c1ccccc1
Product: CCCCC(=O)Nc1cccc(NC(=O)CC(C)=O)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
42 g of diketene were added to a mixture of 96 g of m-aminovaleranilide in 400 ml of benzene and the mixture was stirred for 16 hours at 20° C. The benzene was decanted and the residue was added to refluxing benzene. The mixture was treated with activated carbon and filtered to obtain raw m-valeramido-acetylacetanilide melting at 90° C. Crystallization from ethyl acetate yielded 34 g of pure m-valeramido-acetylacetanilide melting at 116° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[F:15][CH2:16][C:17](=[O:20])[CH2:18][F:19].CC(=O)OCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:17]([OH:20])([CH2:18][F:19])[CH2:16][F:15]
Reactant: Cc1ccc(Br)c(I)c1
Reactant: O=C(CF)CF
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Br)c(C(O)(CF)CF)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 1-bromo-2-iodo-4-methylbenzene (18.5 g, 62.3 mmol) in THF (50 mL) at 0° C. was slowly added i-PrMgCl (12 mL, 23.47 mmol). After stirring for 1 h at 0° C., the reaction temperature was cooled to −70° C. Then a solution of 1,3-difluoropropan-2-one (1.7 g, 18.05 mmol) in dry THF (5 mL) was added. The mixture was stirred at −70° C. for 1 h, and then dry ice bath was removed. The solution was acidified with 2 N HCl and extracted with EA (60 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (25:1) to give the desired product (2.5 g, yield 53%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J=1.8 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.02-6.99 (m, 1H), 5.13-5.09 (m, 1H), 5.02-4.94 (m, 2H), 4.87-4.82 (m, 1H), 3.27 (bs, 1H), 2.33 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:16][O:17][C:18](=[O:25])[CH:19]([CH3:24])[C:20]([NH2:23])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([NH:23][C:20]([CH3:22])([CH3:21])[CH:19]([CH3:24])[C:18]([O:17][CH3:16])=[O:25])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: COC(=O)C(C)C(C)(C)N
Product: COC(=O)C(C)C(C)(C)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 3-amino-2,3-dimethyl-butanoic acid methyl ester (CAN 89855-37-8) as starting materials and isolated (126 mg, 81%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 355.1427 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:20])[C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]#[C:17][CH2:18][OH:19])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C(C)=CC=CC=1C.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:20])[C@H:9]2[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]#[C:17][CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CN(c1ccc(Cl)nn1)[C@H]1CC[C@H](CC#CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CN(c1ccc(Cl)nn1)[C@H]1CC[C@H](CC#CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
A solution of 1.08 g (3.68 mmol) of trans-4-{4-[(6-Chloro-pyridazin-3-yl)-methyl-amino]-cyclohexyl}-but-2-yn-1-ol in 30 ml CH2Cl2 was treated at 0° C. with 0.31 ml (4.04 mmol) methanesulfonylchloride and 0.64 ml (5.51 mmol) 2,6-lutidine. The reaction was stirred for 46 h at room temperature, water (4 ml) was added and stirred for 5 min. After extraction with aqueous saturated NaHCO3/Et2O(3×), the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 1.45 g of crude trans-Methanesulfonic acid 4-{4-[(6-chloro-pyridazin-3-yl)-methyl-amino]-cyclohexyl}-but-2-ynyl ester, MS: 372 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1.O>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:17][CH2:16]2)[C:18]([C:20]2[CH:21]=[N:22][C:23]([N:36]3[CH:40]=[CH:39][N:38]=[CH:37]3)=[N:24][CH:25]=2)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Reactant: c1c[nH]cn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(-n3ccnc3)nc2)C2CC2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (3.00 g), ethyldiisopropylamine (1.97 mL) and 1H-imidazole (520 mg) in N-methyl-2-pyrrolidinon (10 mL) is stirred over night at 100° C. After cooling to room temperature, water is added and the precipitate is filtered off and dried. LC (method 9): tR=1.29 min; Mass spectrum (ESI+): m/z=413 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][N:4]1[C:12]2[NH:11]C=[N:9][C:8]=2[C:7](=[O:13])[N:6]2[CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=[C:5]12.Cl.CSC1NCC(C)(C)N=1.CC(C)CN.ClC1C=CC(CN)=CC=1.N(=C(C#N)C(OCC)=O)[OH:45].S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C(O)=O>[NH2:11][C:12]1[N:4]([CH2:3][CH:2]([CH3:19])[CH3:1])[C:5]2[N:6]([CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=2)[C:7](=[O:13])[C:8]=1[N:9]=[O:45]
Reactant: CC(C)CN1C2=NC(C)(C)CN2C(=O)c2nc[nH]c21
Reactant: CCOC(=O)C(C#N)=NO
Agent: CSC1=NC(C)(C)CN1
Agent: Cl
Agent: NCc1ccc(Cl)cc1
Solvent: O=CO
Solvent: CC(C)CN
Product: CC(C)CN1C2=NC(C)(C)CN2C(=O)C(N=O)=C1N

Procedure:
6,7-DIHYDRO-4-(2METHYLPROPYL)-6,6-DIMETHYL-3H-IMIDAZO[1,2-a]PURIN-9(4H)-ONE.-- 7-Amino-2,3-dihydro-2,2-dimethyl-8-(2-methylpropyl)-6-nitrosoimidazo[1,2-a]pyrimidin-5(8H)-one was prepared by reaction of the 2-methylthio-4,4-dimethyl-2-imidazoline hydrochloride with 2-methylpropylamine according to the method of Procedure 103 by substitution of the latter for p-chlorobenzylamine. The reaction product from this step was then condensed with ethyl oximinocyanoacetate as described in Procedure 103. The resulting nitroso compound was then reduced with sodium dithionate in formic acid and the resulting formylamino compound was cyclized with dilute aqueous sodium hydroxide according to Procedure 100.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:19]=[CH:18][C:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)[CH:3]([CH3:6])[CH2:4][OH:5].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[OH:5][CH2:4][C:3]([CH3:6])=[CH:2][C:7]1[CH:19]=[CH:18][C:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1
Reactant: CC(CO)C(Cl)c1ccc(Cc2cccnc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=Cc1ccc(Cc2cccnc2)cc1)CO
Yield: 62.7 %

Procedure:
In 1.3 ml of N,N-dimethylformamide was dissolved 260 mg of 3-[p-(1-chloro-3-hydroxy-2-methylpropyl)benzyl]pyridine, and 0.28 ml of DBU was added to the resulting solution after which the resulting mixture was subjected to reaction at a temperature of 110° to 120° C. for one hour. To the reaction mixture was added 5 ml of water, and the mixture was subjected to extraction with two 5-ml portions of ethyl acetate. The extracts were combined, washed with 3 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a colomn chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (3:1 by volume)] to obtain 150 mg (yield 62.7%) of colorless, oily 3-[p-(3-hydroxy-2-methyl-1-propenyl)benzyl]pyridine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH:20]=[CH:19][C:18]=2[C:22]=1[C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN(C)[CH:30]=[O:31]>>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH:30]=[O:31])=[CH:19][C:18]=2[C:22]=1[C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2occc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Phosphorus oxychloride (26.2 ml, 0.29 mol) was added dropwise to N,N-dimethylformamide (17 ml, 0.22 mol) under ice cooling; subsequently, a solution of 5-benzyloxy-4-tert-butylbenzofuran (40 g, 0.14 mol) in N,N-dimethylformamide (10 ml) was added dropwise. The mixture was stirred first at room temperature for 20 min, then under heating at 80° C. for 2 h. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-benzyloxy-4-tert-butyl-2-formylbenzofuran [16.2 g (yield, 36%)].
Reaction SMILES: [Br:1][C:2]([Br:5])=[N:3][OH:4].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:4][N:3]=[C:2]([Br:5])[Br:1])=[O:12])=[CH:9][CH:8]=1
Reactant: ON=C(Br)Br
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(ON=C(Br)Br)c1ccc(Cl)cc1
Yield: 0.1 %

Procedure:
A mixture of 3 g (14.78 mole) of dibromoformaldoxime and 2.71 g (15.5 mole) of 4-chlorobenzoyl chloride in methylene chloride (40 ml) is treated with dry pyridine (1.26 g, 16 mole) After workup as in Step B of Example 1 there is obtained 4.4 g (80% theory) of 4-chlorobenzoyldibromoformaldoxime, m.p.=93°-97° C.
Reaction SMILES: [H][H].[OH:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:5]([F:8])([F:7])[F:6]>C(O)(C)C.[Rh]>[OH:3][CH:4]([CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)[C:5]([F:6])([F:7])[F:8]
Reactant: [H][H]
Reactant: Oc1ccc(C(O)C(F)(F)F)cc1
Agent: [Rh]
Solvent: CC(C)O
Product: OC1CCC(C(O)C(F)(F)F)CC1

Procedure:
At 50° C. and a hydrogen pressure of 150 bar, 44.1 g of 4-(1-hydroxy-2,2,2-trifluoroethyl)phenol were hydrogenated in the presence of 3 g of rhodium (5% on carbon) in 500 ml of isopropanol. The catalyst was filtered off and the mixture was concentrated, to give the title product as a colourless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:8]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[Cl:6][C:7]1[C:8]([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH:22]=[O:23])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccnc1-n1cccc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3.8 ml of N,N-dimethylformamide was added dropwise 4.2 ml of phosphorus oxychloride at room temperature, and the mixture was stirred at room temperature for 30 minutes. Thereto 1.6 g of 3-chloro-2-(1H-pyrrol-1-yl)pyridine was added, and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then slowly added to ice-water. The mixture was adjusted to pH 4 by an addition of a 2N aqueous sodium hydroxide solution. A deposited precipitate was collected by filtration to obtain 1.7 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine of the formula:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1)[CH3:2].Cl.O1CCOCC1>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(CN)c1
Reaction time: 20 h

Procedure:
A solution of (3-cyano-phenyl)-acetic acid ethyl ester (6.3 g, 33.29 mmol) in EtOH (50 mL) was added to a mixture of 10% Pd/C (1.26 g) in EtOH (50 mL) under Nitrogen. Additional EtOH (150 mL) was added followed by a solution of HCl in dioxane (4M, 11.4 mL, 45.6 mmol). The mixture was hydrogenated on a Parr shaker at 45 psi for 20 h and the catalyst was removed by filtration through celite. The solution was concentrated to afford (3-aminomethyl-phenyl)-acetic acid ethyl ester as the hydrochloride salt (7.31 g). 1H NMR (400 MHz, CD3OD) δ 7.42-7.32 (m, 4H), 4.12 (q, 2H), 4.09 (s, 2H), 3.68 (s, 2H), 1.23 (t, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([NH:22]C(=O)OC(C)(C)C)[CH:20]=5)[NH:15][C:14]4=[O:30])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:30])[C:13]12[CH2:12][CH:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:43][CH:42]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1(CC1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C5CC56C(=O)Nc5ccc(N)cc56)ccc34)cc2)CC1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
The Suzuki coupling was executed according to the method in Example A45, except substituting tert-butyl 2-(3-iodo-1H-indazol-6-yl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-ylcarbamate (70 mg, 0.136 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (57 mg, 0.190 mmol). The resulting product was dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. After 1 h the reaction was complete, the solvent was removed and the residue purified by prep-HPLC to give a white powder (3.2 mg, 15%); 1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.53 (s, 1 H), 7.18 (d, J=8.8 Hz, 2H), 7.05-7.02 (m, 3H), 6.04 (s, 1H), 4.01-3.97 (bs, 2H), 3.75-3.65 (bs, 2H), 3.46 (t, J=8.4 Hz, 1H), 3.32-3.28 (bs, 2H), 3.18-3.08 (bs, 2H), 3.00 (s, 3H), 2.35-2.31 (m, 1H), 2.29-2.25 (m, 1H); MS ESI [M+H]+ 465.1, calcd for [C28H28N6O+H]+ 465.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[C:15]([C:16]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+].[ClH:33]>C(O)(C)C.O.CN(C)C=O>[ClH:33].[CH3:26][C:25]([CH3:27])=[CH:24][CH2:23][N:19]1[CH2:20][CH2:21][C:16]2([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[O:9][C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]1
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Reactant: CC(C)=CCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)O
Product: COc1cccc2c1Oc1ccccc1C21CCN(CC=C(C)C)CC1

Procedure:
A mixture of 4-methoxyxanthene-9-spiro-4'-piperidine (2.0 g.), 1-bromo-3-methylbut-2-ene (1.15 g.), sodium bicarbonate (0.59 g.) and dimethylformamide (20 ml.) is heated under reflux for 4 hours. The mixture is cooled, poured into water and extracted with chloroform. The chloroform extract is washed with water, dried with MgSO4 and evaporated to give a gummy residue. The residue is dissolved in isopropanol and treated with ethereal hydrochloric acid. The residue is recrystallised from isopropanol-ether to give 1'-(3-methylbut-2-enyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 247°-249° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>ClCCl>[CH2:9]([O:11][C:12](=[O:13])[NH:14][C:15](=[S:16])[NH:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:10]
Reactant: Nc1ncccc1Br
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: CCOC(=O)NC(=S)Nc1ncccc1Br
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 2-amino-3-bromopyridine (50.0 g, 289 mmol, 1 equiv) in dichloromethane (500 mL) was added dropwise ethoxycarbonyl isothiocyanate (39.0 g, 297 mmol, 1.03 equiv) at room temperature. After 2 h, dichloromethane was removed in vacuo to provide crude ethyl[(3-bromopyridin-2-yl)carbamothioyl]carbamate (88 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1>CCO.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3c2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccc3ccccc3c2)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in EtOH (50 mL) and hydrogenated in the presence of 10% Pd/C (300 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(naphthalen-2-yloxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:6]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(Cl)CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(CCCBr)N1CCCc2ccccc21
Reaction time: 3 h

Procedure:
A solution of 4-bromobutyryl chloride (3.4 g) in ether (25 ml) was added to a mixture of 1,2,3,4-tetrahydroquinoline (6.8 g), ether (20 ml) and 10% aqueous sodium hydroxide (34 ml). The mixture was refluxed with stirring for 3 hours then the ethereal solution was washed with dilute hydrochloric acid, dried and evaporated to yield the title compound as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH2:7]
Reactant: COc1ccccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1N
Yield: 16.1 %

Procedure:
0.35 g of tert-butyl-N-(2-methoxyphenyl)carbamate (theoretically 2 mmol/g) bonded on solid support 8 is reacted with 0.5 ml (7 mmol, 10 eq) of a 20% solution of TFA/CH2Cl2 at room temperature for 1 hour. The resin is filtered on a scintered filter and rinsed with CH2Cl2 and MeOH. Then, the filtrate is concentrated under vacuum, taken up in CH2Cl2, washed with a saturated aqueous NaHCO3 solution. After drying on MgSO4 and evaporation of the solvent, 31.1 mg of 2-methoxyaniline is obtained and characterized by the 1H NMR spectrum and compared with the commercial product (yield: 36%). An IR control of the resin showed that the cleavage was not complete (presence of a carbonyl band at 1729 cm−1). The resin was then reacted again with 10 equivalents of a 20% solution of TFA/CH2Cl2 for 15 hours at room temperature. After an identical treatment, 13.8 g of pure 2-methoxyaniline were obtained (overall yield: 52%).