Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:35])[NH:17][CH:18]([C:22](=[O:34])[NH:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])[CH:28]=1)[CH2:19][CH2:20][CH3:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16](=[O:35])[NH:17][CH:18]([C:22](=[O:34])[NH:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([CH3:33])([CH3:32])[CH:30]=[O:31])[CH:28]=1)[CH2:19][CH2:20][CH3:21])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cn(C(C)(C)CO)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cn(C(C)(C)C=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 108.2 %

Procedure:
To a solution of oxalyl chloride (1.2 mL, 14.1 mmol) in 110 mL of methylene chloride at −78° C. is added DMSO (2.2 mL, 30.6 mmol) dropwise. The reaction is stirred for 20 min. and {1-[1-(2-Hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamic acid tert-butyl ester (4.2 g, 11.8 mmol) is added in 10 mL of methylene chloride. The reaction is stirred for 1 h, triethylamine (8.2 mL, 58.9 mmol) is added, and the reaction warmed to 0° C. for 20 min. The reaction is quenched with 100 mL of sodium bicarbonate, extracted with methylene chloride, dried, and concentrated to afford the title compound (4.5 g): MS m/z 353.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]4[N:17]([CH:30]=[CH:31][N:32]=4)[C:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([O:27]CC)[CH:22]=4)=[CH:19][N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH+]1C=CC=CC=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[C:16]4[N:17]([CH:30]=[CH:31][N:32]=4)[C:18]([C:21]4[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=4)=[CH:19][N:20]=3)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCOc1cc(-c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)c3nccn23)ccn1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: CN1CCN(c2ccc(Nc3ncc(-c4cc[nH]c(=O)c4)n4ccnc34)cc2)CC1
Temperature: 150 °C

Procedure:
A mixture of (4-(4-methylpiperazin-1-yl)phenyl)-[5-(2-ethoxypyridin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]amine (103 mg, 0.24 mmol) and pyridinium hydrochloride (130 mg, 1.2 mmol) in water (0.2 mL) is heated at 150° C. for 25 minutes in a sealed tube. After this time the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 92:8 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated to afford the title compound as a solid. HPLC (254 nm): Rt 1.70 min (99.7%); m/z (APCI) 402 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[CH2:6][N:5]2[CH2:16][CH2:17][CH2:18][CH:4]2[C:3]1=[O:19].[H][H]>[Pd].C(O)C>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]2[N:2]([CH3:1])[C:3](=[O:19])[CH:4]3[CH2:18][CH2:17][CH2:16][N:5]3[CH2:6][C:7]=2[CH:12]=1
Reactant: CN1C(=O)C2CCCN2Cc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C2CCCN2Cc2cc(N)ccc21

Procedure:
A mixture of 5.0 g. of 1,2,3,5,10,11a-hexahydro-10- methyl-7-nitro-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11-one, 200 ml. of ethanol and 1.0 g. of 10% palladium-on-carbon catalyst is shaken in a Parr hydrogenator under about 3 atmospheres of hydrogen pressure until the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the mother liquor is concentrated to remove the solvent. The residue is purified by partition chromatography on a diatomaceous earth column using a heptane/methyl cellosolve solvent system to yield pure 7 -amino-1,2,3,5,10,11a-hexahydro-10-methyl-11H-pyrrolo[2,1-c]- [1,4]benzodiazepin-11-one.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1>CO.[Pd]>[NH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][C:2]([CH3:14])([CH3:13])[CH3:1])=[CH:10][N:9]=1
Reactant: CC(C)(C)C#Cc1ccc(C#N)nc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)CCc1ccc(CN)nc1
Yield: 80.1 %

Procedure:
Dissolve 5-(3,3-dimethyl-but-1-ynyl)-2-cyano-pyridine (255 mg, 1.5 mmol) in methanol (15 mL). Add 10% Pd/C (Degussa type E101, 230 mg) and submit the mixture to hydrogenation under atmospheric pressure (balloon) overnight. Filter the catalyst through Celite® and concentrate the filtrate in vacuo to provide the title compound as a solid (231 mg, 87%) that was used without any further purification. MS (ES+) m/z: 193 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[C:20]([O:24][C:25]([NH:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>CO.CC(O)C.C(OCC)(=O)C>[C:20]([O:24][C:25]([NH:27][C@@H:28]1[CH2:32][CH2:31][N:30]([CH:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([OH:15])[CH2:9][CH2:10]2)[CH2:29]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 4-(4-Fluorophenyl)-4-hydroxy-cyclohexanone (2.0 g, 9.6 mmol) and acetic acid (2.6 ml, 48 mmol) in methanol (60 ml) was added (3R)-(+)-3-(tert-butoxycarbonylamino) pyrrolidine (2.6 g, 14.4 mmol). After stirring for 2 hours at room temperature, sodium cyanoborohydride (1M in tetrahydrofuran, 14.4 ml, 14.4 mmol) was added dropwise. The reaction mixture was stirred for 45 minutes, concentrated, diluted with 10% potassium hydrogen sulfate and extracted twice with ether. The aqueous solution was basified with 1N sodium hydroxide and extracted with ethyl acetate three times. Washing with brine, drying and solvent evaporation gave an oil. Flash chromatography (silica gel, 2-propanol-ethyl acetate, 4:96 increasing to 8:92) gave 4-(3-(3R)-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-1-(4-fluorophenyl)-cyclohexanol (2.0 g, 56%); 1H NMR (CDCl3)δ 7.46(m, 2H), 7.02 (m, 2H), 4.89 (m, 1H), 4.18 (m, 1H), 2.94 (m, 1H), 2.71 (m, 2H), 2.42 (m, 1H), 2.26 (m, 1H), 2.13 (m, 1H), 1.83 (m, 9H), 1.63 (m, 1H), 1.44 (s, 9H),
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=[O:18])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:23][C:24]=3[F:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 102.6 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.040 g, 0.18 mmol) obtained in Step C of Preparation Example 23 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.046 g, 0.18 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.069 g, 98%).
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.[F-].[Cs+].Cl[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]2[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][CH:16]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])=[CH:17][CH:16]=2)[CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cccnc3)ccc12
Temperature: 100 °C

Procedure:
900 mg of diethyl-3-pyridylborane, 1.86 g of caesium fluoride, 18.4 mg of palladium acetate and finally 48 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1.5 g of N-[6-chloro-1-[[2(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 40 cm3 of dioxane. The mixture is then heated at about 100° C. for 17 hours and then filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 75 cm3 of ethyl acetate and 50 cm3 of distilled water. The organic phase is washed again with 50 cm3 of distilled water and with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure under the conditions described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume) and collecting 25 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 900 mg of N-[6-(3-pyridyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]([N:4]1C=C(CCNC(NC2SC(C3C=C(C)N=C(SC)N=3)=C(C)N=2)=O)N=[CH:5]1)([CH3:3])[CH3:2].C(C1O[C:35]([CH2:37][CH2:38][NH:39][C:40]([NH:42][C:43]2[S:44][C:45]([C:49]3[CH:54]=[C:53]([CH3:55])[N:52]=[C:51]([S:56]([CH3:59])(=[O:58])=[O:57])[N:50]=3)=[C:46]([CH3:48])[N:47]=2)=[O:41])=[N:34][CH:33]=1)C>>[CH:1]([N:4]1[CH:5]=[C:35]([CH2:37][CH2:38][NH:39][C:40]([NH:42][C:43]2[S:44][C:45]([C:49]3[CH:54]=[C:53]([CH3:55])[N:52]=[C:51]([S:56]([CH3:59])(=[O:57])=[O:58])[N:50]=3)=[C:46]([CH3:48])[N:47]=2)=[O:41])[N:34]=[CH:33]1)([CH3:3])[CH3:2]
Reactant: CSc1nc(C)cc(-c2sc(NC(=O)NCCc3cn(C(C)C)cn3)nc2C)n1
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)(=O)=O)n3)s2)o1
Product: Cc1cc(-c2sc(NC(=O)NCCc3cn(C(C)C)cn3)nc2C)nc(S(C)(=O)=O)n1

Procedure:
This material is prepared from 1-[2-(1-isopropyl-1H-imidazol-4-yl)-ethyl]-3[4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-urea by the same protocol described for 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfonyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 41).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][C:7](=[O:9])[CH3:8])[C:3](=[O:5])[CH3:4].C1C2B3C(CCC2)CCCC3CC1.[Li]>O1CCCC1>[CH3:1][C:2]([CH3:10])([CH2:6][CH:7]([OH:9])[CH3:8])[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CC(C)(C)C(C)=O
Agent: C1CC2CCCC3CCCC(C1)B23
Agent: [Li]
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)CC(C)O
Temperature: 0 °C
Yield: 90 %

Procedure:
In a flask is placed 100 mmoles of 3,3-dimethyl-2,5-hexanedione in 50 ml. of tetrahydrofuran. The reaction mixture is cooled to 0° C. and 100 mmoles of lithium perhydro-9b-boraphenalylhydride is added slowly. A 90% yield of 3,3-dimethyl-5-hydroxy-2-hexanone is obtained.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:20])[CH2:5][N:6]([CH2:17][CH:18]=[CH2:19])[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Cl:16])[N:8]=1>[Fe].C(O)(=O)C>[CH2:17]([N:6]1[CH2:5][CH:4]([CH3:20])[C:3](=[O:2])[NH:13][C:12]2[CH:11]=[N:10][C:9]([Cl:16])=[N:8][C:7]1=2)[CH:18]=[CH2:19]
Reactant: C=CCN(CC(C)C(=O)OC)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: C=CCN1CC(C)C(=O)Nc2cnc(Cl)nc21
Yield: 277 %

Procedure:
To a solution of 2.55 g (0.002 mole) of (rac)-3-[allyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-2-methyl-propanoic acid methyl ester (IV-65) and 20 mL of acetic acid, was added 2.55 g (0.0457 g-atom) of iron powder. The mixture was heated at 80 degrees for 2 hours and then filtered through Celite while still hot. The filter cake was washed with 100 mL of ethyl acetate. The filtrate was washed successively with 100 mL of water, 100 mL of 7.4 M ammonium hydroxide, 100 mL of water and 100 mL of brine. The aqueous layers were back extracted with 100 mL of ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane—hexanes to give 1.40 g of (rac)-9-allyl-2-chloro-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-65) as off-white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
A solution of (3,4-dichloro-phenyl)-acetic acid (14.0 g, 0.07 mol) in methanol (71 mL) was treated with a catalytic amount of concentrated sulfuric acid. The reaction mixture was heated under reflux for 12 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3,4-dichloro-phenyl)-acetic acid methyl ester (15.0 g, quant.) as a white solid: mp 30-32° C.; EI-HRMS m/e calcd for C9H8Cl2O2 (M+) 217.9901. found 217.9907.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[NH:62][C:63](=[O:65])[CH3:64])[CH:53]=[CH:54][CH:55]=1>CN(C=O)C>[C:63]([NH:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([NH:49][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:51]=1)(=[O:65])[CH3:64]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 415 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH2:37]O)[CH2:36][O:35][CH2:34][O:33][CH2:32]1.[K+].[Br-].Cl>>[CH3:30][C:31]1([CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:37][C:31]3([CH3:30])[CH2:32][O:33][CH2:34][O:35][CH2:36]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:36][O:35][CH2:34][O:33][CH2:32]1
Reactant: CC1(CO)COCOC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1(C)COCOC1)(C(=O)OCC1(C)COCOC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 5-methyl-[1,3]dioxan-5-ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) 6 0.7 (s, 3H, CH3), 0.74 (s, 3H, CH3), 1.1 (d, J=6.59 Hz, 3H, CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 8H, CH, CH2), 3.6-3.7 (m, 4H, CH2), 4.6-4.8 (m, 4H, CH2), 5.04 (m, 1H, CH), 6.34 (brs, 1H, OH), 6.84 (dd, J=8.13, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.36-7.44 (m, 3H, Ar--H), 7.48 (s, 1H, Ar--H), 8.77 (brs, 1H, NH), 9.2 (brs, 1H, NH); IR (KBr, cm-) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 650 (M+H)+; Analysis for: C32H40ClNO11 ×HCl: Calc'd: C, 55.98; H, 6.02; N, 2.04; Found: C, 54.67; H, 6.58; N, 2.05.
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([CH2:9][CH2:10][CH3:11])[C:4](=[N:7][OH:8])[CH2:5][CH3:6].[ClH:14].ClCl>C(Cl)Cl>[Cl:14][CH:9]([CH2:10][CH3:11])[C:3]([O:2][CH3:1])([O:12][CH3:13])[C:4](=[N:7][OH:8])[CH2:5][CH3:6]
Reactant: Cl
Reactant: CCCC(OC)(OC)C(CC)=NO
Agent: ClCl
Solvent: ClCCl
Product: CCC(=NO)C(OC)(OC)C(Cl)CC

Procedure:
Following the general procedure of Example 1, to a solution of 4.73 parts of 4,4-dimethoxy-3-oximinoheptane and 0.2 parts anhydrous hydrogen chloride dissolved in 20 parts dry methylene chloride, at 30 to 35° C., under a dry nitrogen atmosphere, was added 1.8 parts of elemental chlorine over a 1/2-hour period. After the addition, the contents were stirred for 1/2-hour and then treated according to the procedure in Example 1 to yield 3.5 parts of 5-chloro-4,4-dimethoxy-3-oximinoheptane as determined by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O[C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13](=[O:15])[O:14][C:21]3[C:18]([CH:19]=2)=[CH:17][CH:24]=[C:23]([OH:25])[CH:22]=3)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(CC(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCCCOc1ccc(-c2cc3ccc(O)cc3oc2=O)cc1
Temperature: 0 °C

Procedure:
89.5 g (0.43 mol) of 4-butoxyphenylacetic acid (prepared by the method of McElvain, Carney; J. Am. Chem. Soc. 1946 (68), 2592-2599) and 30.0 g (0.22 mol) of 2,4-dihydroxybenzaldehyde are heated at 120° C. for 5 h in 100 ml of acetic anhydride and 120 ml of triethylamine. The still-hot solution is subsequently added to 3 l of ice-water, and the precipitated product is filtered off with suction and suspended in 1 l of water and 1.4 l of ethanol. After dropwise addition of 190 ml of conc. sulfuric acid, the batch is heated under reflux for 4 h and added to 3 l of water, and the precipitated product is filtered off with suction. The crude product is filtered through silica gel with hot toluene/ethyl acetate (1:1), the solvent is evaporated in vacuo, and the residue is recrystallised from toluene, giving 3-(4-butoxyphenyl)-7-hydroxychromen-2-one as colourless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([CH3:11])[N:5]=[C:4]([NH2:12])[N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CCC>[CH2:13]([N:20]1[C:2]2[N:3]=[C:4]([NH2:12])[N:5]=[C:6]([CH3:11])[C:7]=2[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(N)nc(Cl)c1CCCl
Reactant: NCc1ccccc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc2c1CCN2Cc1ccccc1

Procedure:
Thus, for example, J. Med. Chem. 2000, 43, 3837-3851 describes the cyclization of 4-chloro-5-(2-chloroethyl)-6-methylpyrimidine-2-amine with benzylamine in the presence of triethylamine and n-butanol to give 7-benzyl-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2-amine.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[C:8]#[N:9].[NH3:18]>>[NH2:18][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[C:8]#[N:9]
Reactant: COc1cc(-c2ccccc2)cc(F)c1C#N
Reactant: N
Product: COc1cc(-c2ccccc2)cc(N)c1C#N
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 3-fluoro-5-methoxy-[1,1′-biphenyl]-4-carbonitrile (3, 4.0 g, 17.6 mmol) in ammonia saturated DMSO (100 mL) was heated in an autoclave at 150° C. for 18 h. After this time, the mixture was cooled to room temperature, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (2.06 g, 52%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ7.54-7.52 (m, 2H), 7.46-7.43 (m, 2H), 7.41-7.38 (m, 1H), 6.52 (d, J=1.0 Hz, 1H), 6.43 (d, J=1.0 Hz, 1H), 4.43 (br s, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]CC2C=CC=CC=2)[N:8]([CH3:25])[N:7]=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[N:8]([CH3:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)n(C)n1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(-c2ccccc2O)n(C)n1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.25 g, 0.00078 mole) in DMF (5 mL) was added K2CO3 (0.225 g, 0.00163 mole) followed by methyl iodide (0.116 g, 0.00081 mole) and at the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then quenched with iced water and the resulting precipitate was isolated by filtration. The solid was recrystallized from ethyl acetate to afford 0.251 g (96%) of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 337.15 (M+1)+, 90.13%. To a stirred solution of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.251 g, 0.00075 mole) in methanol (40 mL) was added 10% Pd/C (0.05 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was then filtered through celite and the celite was washed with methanol. The combined filtrate was concentrated under reduced pressure to afford 0.169 g (92%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 247.1 (M+1)+, 99%. To a stirred solution of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.169 g, 0.00069 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL), was added LiOH.H2O (0.087 g, 0.00206 mol) at ambient temperature and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and acidified with 10% HCl. The product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.13 g (87%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. LCMS: 219.07 (M+1)+, 81.5%
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:23][C:24]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:23]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1)=[CH2:24]
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Yield: 85 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-spiro [cyclopropane-1,3′-indolin]-2′-one (802 mg, 2 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (462 mg, 3 mmol) in a 20 mL microwave vial was added PhCH3/EtOH (8 mL/4 mL), followed by 1 M Na2CO3 (3 mL, 3 mmol) and Ph(PPh3)4 (46 mg, 0.04 mmol, 2 mol %) was added and the resulting mixture was purged with argon, then microwaved 3 h at 120° C. After aqueous workup, the solution was extracted with EtOAc and was purified by flash chromatography (Hex/EtOAc 1:1) to give the crude title compound as a light yellow foam (512 mg) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.10-6.88 (m, 5H), 6.54 (t, J=7.4 Hz, 1H), 6.06 (d, J=18.0 Hz, 1H), 5.92 (d, J=7.6 Hz, 1H), 5.49 (d, J=7.6 Hz, 1H), 3.46 (d, J=8.2 Hz, 1H), 2.30-2.18 (m, 2H); MS ESI 302.0 [M+H]+, calcd for [C19H15N30+H]+ 302.1.