Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[N+:12]([C:15]1([CH2:21][CH2:22][C:23](=[S:25])[NH2:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-:14])=[O:13]>>[N+:12]([C:15]1([CH2:21][CH2:22][C:23]2[S:25][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: NC(=S)CCC1([N+](=O)[O-])CCCCC1
Reactant: O=C1c2ccccc2CC1Br
Product: O=[N+]([O-])C1(CCc2nc3c(s2)Cc2ccccc2-3)CCCCC1

Procedure:
2-Bromo-1-indanone, 3-(1-nitrocyclohexyl)propanethioamide
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[F:27][C:28]1[N:33]=[CH:32][C:31]([C:34]2([CH2:40]O)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>ClCCl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2([CH2:40][I:20])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:32][N:33]=1
Reactant: OCC1(c2ccc(F)nc2)CCOCC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(C2(CI)CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To an ice cooled solution of triphenylphosphine (983 mg, 3.75 mmol), iodine (952 mg, 3.75 mmol) in dichloromethane (20 mL) was added imidazole (278 mg, 4.09 mmol). The solution was stirred at ambient temperature for 1 h, followed by the addition of (4-(6-fluoropyridin-3-yl)tetrahydro-2H-pyran-4-yl)methanol (360 mg, 1.70 mmol) in 10 mL dichloromethane. The reaction mixture was heated to 60° C. in an oil bath for 48 h. Solid was filtered off, the filtrate was purified by flash column chromatography on silicagel (ISCO) eluting with 0-80% ethyl acetate in heptane to give to give 2-fluoro-5-(4-(iodomethyl)tetrahydro-2H-pyran-4-yl)pyridine (330 mg, 1.03 mmol, 60.3% yield) as light yellow color oil. LCMS (m/z): 322 (MH+), 0.77 min.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](F)[C:29]=1[Cl:35].Cl.CCO>>[Cl:27][C:28]1[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=1[O:19][C@@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH:14]([CH2:15][CH3:16])[CH2:17][CH3:18]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CCC(CC)[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCC(CC)[C@@H](Oc1cccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethyl-1-hydroxybutyl)pyrrolidine-1-carboxylic acid t-butyl ester (28 mg, 0.1 mmol) was dissolved in DMF (380 μL, 4.9 mmol). 60% Sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 18.6 mg, 310 μmol) was slowly added, and the resulting mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (23.8 μL, 206 μmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated, treated with 1.25M HCl in EtOH (578 μL, 722 μmol), then stirred overnight at room temperature. The product was concentrated under vacuum, redissolved in 1:1AcOH:H2O, filtered, and purified by preparative HPLC to yield the title compound as a mono-TFA salt (5.3 mg, 97% purity). MS m/z: [M+H] calcd for C16H23Cl2NO, 316.12. found 316.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:35][N:36]2[CH2:41]CN[CH2:38][CH2:37]2)=[C:21]2[C:25]=1[N:24]([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:23]=[CH:22]2.Cl.N1CCC1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:36]1([CH2:35][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[C:25]3[C:21]=2[CH:22]=[CH:23][N:24]3[S:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH2:41][CH2:38][CH2:37]1
Reactant: COc1ccc(CN2CCNCC2)c2ccn(S(=O)(=O)c3ccccc3)c12
Agent: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCC2)c2ccn(S(=O)(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzenesulfonyl-7-methoxy-1H-indole-4-carbaldehyde (20 mg, 0.06 mmol prepared as in Example 79) azetidine hydrochloride (30 mg, 0.32 mmol) and sodium acetate (26 mg, 0.32 mmol) were mixed in 1,2-dichloroethane (1 mL), and stirred at 40° for 1 h, cooled to room temp followed by addition of sodium triacetoxyborohydride (22 mg, 0.1 mmol). The mixture was stirred over night. No remaining starting material according to LCMS. The mixture was evaporated, dissolved in DMF, filtered an purified on prep HPLC YMC 40 mL/min 22-50 mL MeCN over 16 min. Obtained 9.8 mg (43%). MS ESI+ for C19H20N2O3S m/z 357 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[C:18](=O)([O-])[O-:19].[K+].[K+].C([B-](F)(F)F)=C.[K+].ClCCl>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C1COCC1>[CH:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1)=[O:19]
Reactant: COC(=O)c1cc(Br)c2ccccc2c1OC
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C=O)c2ccccc2c1OC
Temperature: 65 °C

Procedure:
To a solution of methyl 4-bromo-1-methoxy-2-naphthoate (see Example 2, 5.00 g, 16.9 mmol) in a 105 mL of a 20:1 mixture of THF:water under an atmosphere of nitrogen was added potassium carbonate (2.58 g, 18.6 mmol), potassium vinyltrifluoroborate (3.40 g, 25.4 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (1.24 g, 1.69 mmol). The reaction was heated at 65° C. for 65 hours, cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The filtrate was concentrated in vacuo to provide methyl 4-formyl-1-methoxy-2-naphthoate that gave a mass ion (ES+) of 242.3 for [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O1CCCC1>[OH:8][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([CH:9]=[O:10])=[CH:2][CH:1]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCCCCCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.2 %

Procedure:
Terephthaldicarboxaldehyde (2.00 g, 14.91 mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to 0° C. Octylmagnesium chloride (7.5 mL, 2.0M in THF, 15 mmol) was added dropwise. After 15 min, the reaction was quenched with 2N aqueous hydrochloric acid (50 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated, washed with sat'd sodium chloride (50 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 9% ethyl acetate/hexane gave 0.19 g (0.77 mmol, 5.1%) of product: 1H NMR (500 MHz) δ 10.0 (s, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 4.75-4.80 (m, 1H), 1.68-1.82 (m, 2H), 1.22-1.45 (m, 12H), 0.91 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].Cl>CO.O>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:21]([OH:20])[CH:22]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.028 g, 0.1 mmol) in MeOH: H2O (1.8: 0.2 mL) was added 3-hydroxyaniline (0.033 g, 0.3 mmol) and heated in a sealed tube at 100° C. for 24 h. The resulting reaction was diluted with H2O (10 mL), acidified with 2N HCl (pH>2), saturated and the resulting solid was filtered to give the desired product, N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl))-2,4-pyrimidinediamine (R926210). Purification can be done by filtration through a pad of silica gel using 1-5% MeOH in CH2Cl2 or by crystallization using an appropriate solvent system. 1H NMR (CDCl3+CD3OD): δ 7.76 (bs, 1H), 7.30 (d, 1H, J=2.4 Hz), 7.10 (m, 1H), 7.03 (t, 1H, J=8.1 Hz), 6.89 (dd, 2H, J=2.4 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.42 (dd, 1H, J=2.4 and 9 Hz), 4.22 (m, 4H); 19F NMR (CDCl3+CD3OD): −47196; LCMS: ret. time: 19.55 min.; purity: 95%; MS (m/e): 355 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8](O)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)(Cl)=O.[CH:27](Cl)(Cl)[Cl:28]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:27][Cl:28])[CH2:3][CH2:2]1
Reactant: ClC(Cl)Cl
Reactant: Oc1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: FC(F)Oc1ccc(CCl)cc1OCC1CC1

Procedure:
A solution of crude 3-cyclopropylmethoxy-4-difluoromethoxyphenyl alcohol (24.4 g) and pyridine (9.8 mL, 120 mmol) in chloroform (150 mL) under an argon atmosphere was treated with thionyl chloride (8.0 mL, 110 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil (26 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]([CH3:27])[C:15]1[CH:16]=[CH:17][C:18]([CH3:26])=[C:19]([CH:25]=1)[C:20]([N:22]([CH3:24])C)=[O:21].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)C#N>C1COCC1>[CH3:27][N:14]([CH3:13])[C:15]1[CH:25]=[C:19]2[C:18]([CH:26]=[C:24]([C:36]3[CH:35]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:37]=3)[NH:22][C:20]2=[O:21])=[CH:17][CH:16]=1
Reactant: COc1cccc(C#N)c1
Reactant: Cc1ccc(N(C)C)cc1C(=O)N(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(-c2cc3ccc(N(C)C)cc3c(=O)[nH]2)c1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a solution of diisopropylamine (1.5 g, 15 mmol) in dry THF (10 mL) was added n-BuLi (6 mL of 2.5 M in hexane, 15 mmol) at −78° C. After 30 min, a solution of 5-dimethylamino-2,N,N-trimethylbenzamide (2.06 g, 10 mmol) in THF (15 mL) was added dropwise at −78° C., the red orange solution was stirred at the same temperature for 1 h. The solution of 3-methoxybenzonitrile (1.7 g, 13 mmol) in dry TIM (10 mL) were added and the reaction mixture was stirred at −78° C. for 2 h. The reaction solution was quenched with water and extracted with ethyl acetate and dried over sodium sulfate. After removing the solvent, the residue was purified by column chromatography with n-hexane-ethyl acetate (3:1) to afford compound I as yellow solid (596 mg, 20%). 1H NMR (300 MHz, CDCl3) δ: 9.73 (s, 1H), 7.61 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.38 (m, 1H), 7.23-7.22 (m, 3H), 6.96 (m, 1H), 6.74 (s, 1H), 3.90 (s, 3H), 3.09 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CCCCI
Agent: [H-]
Agent: [Li+]
Product: CCCCn1c(=Nc2ccc(C)cc2)sc2ncccc2c1=O
Yield: 52 %

Procedure:
The reaction procedure of Example 11 was followed except that 909 mg (3.38 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 27 mg of lithium hydride and 621 mg of butyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 571 mg of 3-butyl-2,3-dihydro-2-[(4-methylphenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (52%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 157 mg of 2-[N-butyl-N-(4-methylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([NH2:24])=[N:21]3)=[N:16][CH:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:25]([N:27]=[C:28]=[S:29])[CH3:26]>N1C=CC=CC=1>[CH2:25]([NH:27][C:28]([NH:24][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][C:14]([NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:15][N:16]=2)[N:21]=1)=[S:29])[CH3:26]
Reactant: CCN=C=S
Reactant: COc1cc(Nc2cnc3ccc(N)nc3c2)cc(OC)c1OC
Solvent: c1ccncc1
Product: CCNC(=S)Nc1ccc2ncc(Nc3cc(OC)c(OC)c(OC)c3)cc2n1
Temperature: 140 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
In a sealed reactor, 88 mg (269 μmol, 1 eq) of N*7*-(3,4,5-trimethoxy-phenyl)-[1,5]naphthyridine-2,7-diamine and 48 μL (538 μmol, 2 eq) of ethyl isothiocyanate were introduced in 3 mL of pyridine. The mixture was stirred at 140° C. for 24 h. The mixture was allowed to reach rt and the solvent was removed under reduced pressure. The residue was purified by column chromatography using methylene chloride/ethanol: 96/4 as eluent. The solvent was evaporated to dryness to afford 56 mg of yellow powder with 51% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>>[NH2:1][C:2]1[CH:7]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Product: Nc1cc(Sc2ccc(Cl)cc2)nc(-c2ccccc2)n1
Temperature: 150 °C

Procedure:
A mixture of 5.14 g. of 4-amino-6-chloro-2-phenylpyrimidine and 10.1 g. of p-chlorothiophenol is heated in an oil bath maintaining a temperature of 150°C. for twenty minutes. The reaction mixture is triturated with hot 10°/o sodium hydroxide. The product is collected on a filter, and washed with water repeatedly. The crude product weighs 8.0 g. and melts at 118°-121°C. Upon recrystallization from cyclohexane, there is obtained 4-amino-6-(4-chlorophenylthio)-2-phenylpyrimidine, m.p. 124°-125°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:18]2[CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:19]2)[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Product: CC(C)(C)OC(=O)N1CC(n2ccc(Br)cc2=O)C1

Procedure:
The title compound was prepared from 4-bromopyridin-2(1H)-one and 3-iodo-azetidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 22.
Reaction SMILES: [CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[CH:13]=[C:12]2[C:4]=1[CH2:5][CH2:6][C:7]1([O:11]2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].[CH3:19][O:20]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[C:13]([CH:19]=[O:20])=[C:12]2[C:4]=1[CH2:5][CH2:6][C:7]1([O:11]2)[CH2:8][CH2:9][CH2:10]1)[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCc1cc2c(c(CC)c1O)CCC1(CCC1)O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1c(O)c(CC)c2c(c1C=O)OC1(CCC1)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
To a solution of 5,7-diethylspiro[chroman-2,1′-cyclobutan]-6-ol (900 mg) in dichloromethane (5 mL) was added titanium tetrachloride (670 mg, 0.4 mL) and dichloromethyl methyl ether (505 mg, 0.39 mL). The solution was stirred at room temperature for 5 hours. The reaction was quenched using diluted hydrochloric acid. Work up and chromatography (silica gel, ethyl acetate in hexane 5%) gave 680 mg of 5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutane]-8-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][O:31][CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[N:22]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc(OC[C@@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: COCC(=O)O
Product: COCC(=O)N1C[C@H](O)C[C@H]1COc1cc(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Yield: 91 %

Procedure:
The procedure described in Example 25 was repeated using (3R,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with methoxyacetic acid (42 μl) to give the title compound as a white solid in 91% yield; NMR spectrum (DMSO-d6) 9.96 (s, 1H), 8.45 (s, 1H), 8.17-8.14 (m, 1H), 7.76-7.72 (m, 1H), 7.45 (t, 1H), 6.83 (s, 2H), 5.10 (m, 1H), 4.73-4.69 (m, 1H), 4.47-4.38 (m, 2H), 4.25 (dd, 1H), 4.10-3.98 (m, 2H), 3.94 (s, 3H), 3.51 (dd, 1H), 3.40 (s, 1H), 3.29 (s, 3H), 2.05-2.02 (m, 2H); Mass spectrum MH+ 491.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]([CH3:26])([CH3:25])[CH2:7][C:8]1[N:9]([CH2:22][CH2:23][CH3:24])[N:10]=[C:11]2[C:20]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]=[C:12]2[NH2:21].C(N(CC)CC)C.Cl>ClCCl.CO>[NH2:21][C:12]1[C:11]2=[N:10][N:9]([CH2:22][CH2:23][CH3:24])[C:8]([CH2:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])([CH3:26])[CH3:25])=[C:20]2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(C)=O
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 72.9 %

Procedure:
Acetyl chloride (221 μL, 3.14 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 840 mg, 2.82 mmol) and triethylamine (591 μL, 4.24 mmol) in dichloromethane (25.2 mL). The solution was stirred for 20.5 h at ambient temperature, then was concentrated under reduced pressure to yield a foam that was dissolved in methanol. To the solution was added concentrated hydrochloric acid (2 mL). The solution was stirred at ambient temperature for 90 minutes, then heated at reflux for 40 minutes. After cooling to ambient temperature, the solution was concentrated under reduced pressure and 2 M aqueous sodium carbonate was added until the pH was basic. The solution was extracted with chloroform. The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), then triethylamine (786 mL) and acetyl chloride (300 mL) were added. The reaction was worked up as before, then methanol (20 mL) and concentrated hydrochloric acid (2 mL) were added. The solution was heated at reflux for 30 minutes, left to stand at ambient temperature overnight, then heated at reflux again for 30 minutes. After cooling to ambient temperature, the solution was concentrated under reduced pressure and 2M aqueous sodium carbonate was added until the pH was adjusted to pH 10-11. The solution was extracted with chloroform three times. The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified twice by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 20-30% CMA in chloroform for the first column; gradient elution with 4-10% methanol in chloroform for the second column). The appropriate fractions were combined and concentrated under reduced pressure to yield a colorless foam that was crystallized from ethyl acetate/hexanes. A white solid was isolated and dried under vacuum at elevated temperature to yield 698 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as a white solid, mp 182-183° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2Cl)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (84 mg, 91%), MS (ISP) m/z=370.4 [(M+H)+], mp 253° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16](Cl)=[O:17])[CH:5]=[CH:4][C:3]1=2.[OH:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25]>>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([O:20][C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=3)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: C=CCOC(=O)c1cccc(O)c1
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Product: C=CCOC(=O)c1cccc(OC(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)c1

Procedure:
In a similar manner to that of Example 1(d), by reaction of 2.8 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyl chloride with 1.8 g (10 mmol) of allyl 3-hydroxybenzoate, 2.6 g (62%) of the expected allyl ester are obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH:49][CH3:50])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl.CN(C=O)C>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][N:49]([CH3:50])[C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=2)=[O:22])=[CH:46][CH:47]=1
Reactant: CNCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCCN4)cc3)co2)c(C)c1
Temperature: 25 °C

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.09 mmol) was dissolved in DCE (2 mL) and CDI (30 mg, 0.18 mmol) added. The reaction was stirred at room temperature until complete as determined by LCMS. 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine (32 mg, 0.17 mmol) and DIPEA (0.032 mL, 0.18 mmol) was added and the reaction stirred for 3 days at ambient temperature. A further 32 mg 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine was added, followed by DMF (0.5 mL) and the reaction was stirred for 18 h. The reaction was washed with saturated aqueous NH4Cl (3×5 mL) and the organic layer dried over MgSO4, shaken with PL-MIA and Ambersep resins, and concentrated. A portion of the crude product was purified using prep method C.