Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)OC(=O)CC1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:12]#[N:13].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]#[N:13])[CH:14]=[CH:15][C:16]=1[CH2:17][Br:18]
Reactant: Cc1ccc(C#N)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: N#Cc1ccc(CBr)c(Cl)c1

Procedure:
The preferred compound α-t-butylamino-3-chloro-4-γ-hydroxypropylpropiophenone hemisuccinate, compound 3, ##STR7## (and suitable analogs and derivatives as would be obvious in view thereof) is prepared by reaction of α-t-butylamino-3-chloro-4-(3-hydroxypropyl)propiophenone hydrochloride three-fourths hydrate, compound 5, ##STR8## with succinic anhydride in pyridine to form the o-hemisuccinate. Intermediate compound 5 is suitably prepared from readily available starting materials. Accordingly, 3-chloro-4-methyl-benzonitrile, N-bromosuccinimide and benzoyl peroxide react at reflux with illumination to give 2-chloro-4-cyanobenzyl bromide. The product compound can be reacted with diethyl malonate in a solution of sodium in ethanol to give diethyl 2-(2-chloro-4-cyanobenzyl)malonate which, upon subsequent treatment with sodium chloride and water in DMSO produces ethyl 3-(2-chloro-4-cyanophenyl)propanoate. Treatment with suitable base, such as potassium hydroxide and alcoholic solvent gives the corresponding propanoic acid, 3-(2-chloro-4-cyanophenyl)propanoic acid which is then reduced to the corresponding alcohol, such as by treatment with B2H6 in tetrahydrofuran (THF). A mixture of the alcohol, 3-(2-chloro-4-cyanophenyl)propanol and ethyl magnesium bromide in dry ethyl ether is reacted at reflux to give 3-chloro-4-(3-hydroxypropyl)propiophenone which yields compound 5 upon bromination to α-bromo-3-chloro-4-(3-hydroxypropyl)propiophenone and subsequent reaction of the bromoketone with an excess of t-butylamine in suitable solvent, such as CH3CN.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]([CH:14]3[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:18].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:14][CH2:15][CH2:16][Br:18])=[CH:4][C:3]=2[O:2]1
Reactant: BrP(Br)Br
Reactant: OC(CCc1ccc2c(c1)OCO2)C1CC1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: BrCCC=CCCc1ccc2c(c1)OCO2

Procedure:
6-(3,4-Methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 11.5 g. of 2-(3,4-methylenedioxyphenyl)ethyl cyclopropyl carbinol (Preparation B2), 12 g. of phosphorus tribromide, 10 g. of lithium bromide and 12.7 g. of zinc bromide according to the procedure given above in Preparation C1, affording 12.5 g. of product as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]([F:47])([F:46])C1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1>>[F:27][C:28]([F:47])([F:46])[C:24]1[CH:23]=[CH:22][C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(C(F)(F)F)cc2)O3)nc1

Procedure:
2-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 605 mg of 2-(4-trifluoromethylphenyl)chroman-6-ol. The product was purified column chromatography using 1.5% ethyl acetate in toluene as an eluant and then crystallised from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.79 (d, 2H, J 8.2 Hz), 7.70 (d, 1H, J 8.2 Hz), 7.21 (d, 1H, J 9.1 Hz), 7.01 (dd, 1H, J 8.7, 2.7 Hz), 6.98 (d, 1H, J 2.7 Hz), 6.95 (d, 1H, 8.7 Hz), 5.29 (dd, 1H, J 10.1, 2.0 Hz), 3.00 (ddd, 1H, J −16.9, 10.1, 5.8 Hz), 2.4 (ddd, 1H, J −16.9, 8.4, 4.5 Hz), 2.24 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: C([CH:8]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][NH:21][C:22]([CH:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[N:26]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]3[NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:25]2[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][C:47]=2[Cl:53])=[O:23])[N:14]=1)[C:9]([O-:11])=[O:10])C1C=CC=CC=1.CN(C=O)C>[Pd].C(O)C>[Cl:53][C:47]1[CH:48]=[C:49]([Cl:52])[CH:50]=[CH:51][C:46]=1[CH:25]1[CH:24]([C:22]([NH:21][CH2:20][CH2:19][C:15]2[N:14]=[C:13]([O:12][CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:17][CH:16]=2)=[O:23])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[N:26]1[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[NH:41][S:42]([CH3:45])(=[O:43])=[O:44]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCc2cccc(OC(Cc3ccccc3)C(=O)[O-])n2)C1c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCc2cccc(OCC(=O)O)n2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a mixed liquid of 420 mg of benzyl({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetate, 5 ml of DMF, and 5 ml of ethanol was added 84 mg of 5% palladium/carbon, followed by stirring at room temperature for 15 minutes under a hydrogen atmosphere. After separating the palladium/carbon by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 78 mg of ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetic acid as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][N:24]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[CH3:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][N:2]2[CH2:7][CH2:6][CH:5]([C:8]3[N:13]=[C:12]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)[N:11]=[C:10]([OH:20])[CH:9]=3)[CH2:4][CH2:3]2)=[CH:25][N:24]=1
Reactant: Oc1cc(C2CCNCC2)nc(N2CCCCC2)n1
Reactant: CNc1ncc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CNc1ncc(CN2CCC(c3cc(O)nc(N4CCCCC4)n3)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A mixture of 6-piperidin-4-yl-2-piperidin-1-yl-pyrimidin-4-ol, hydrochloride salt (2.0 mmol), 2-methylaminopyrimidine-5-carbaldehyde (2.6 mmol), triethylamine (4.0 mmol) and 3 drops of acetic acid in dry dichloromethane (20 mL) was stirred at room temperature for 3 hours. Then sodium triacetoxyborohydride (6.0 mmol) was added in portions and stirring was continued for 48 hours (monitored by TLC). The mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL), and the product was extracted with dichloromethane (2×10 mL). The extracts were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give a crude product. Purification via column chromatography (silica gel, ethyl acetate/hexane) afforded 6-[1-(2-methylaminopyrimidin-5-ylmethyl)-piperidin-4-yl]-2-piperidin-1-yl-pyrimidin-4-ol (Compound IIc, 637 mg, 83%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:26][C:27]1[C:32]([NH2:33])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[NH2:33][C:32]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[F:26]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc(F)c(N)c2)OC1(C)C
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(F)c(N)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (stage 149.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.53 min (Method A); M+H=485 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.20 (s, 1H), 8.12-8.08 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.44 (m, 1H), 7.29-7.23 (m, 2H), 5.57 (s, br, 2H), 4.54 (hp, 1H), 3.58 (s, 3H), 1.95 (s, 3H), 1.44 (d, 6H))
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:19][CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>C1COCC1>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24])[CH3:28]
Reactant: O=S(=O)([O-])CCCCCl
Reactant: CCNCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCN(CC)CCCCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tetrabutylammonium-4-chlorobutylsulfonate in THF sodium carbonate is added. To the resulting suspension, a solution of diethylamine in THF is added. The suspension is stirred at room temperature for 1 h. The precipitate is filtered off and the remaining solution is concentrated with a rotary evaporator to yield tetrabutylammonium-4-diethylaminobutylsulfonate.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[C:16]([CH3:17])=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1.O>C1COCC1>[Br:7][C:8]1[C:16]([CH3:17])=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CO)ccc1Br
Reaction time: 0.25 h
Yield: 100 %

Procedure:
LiAlH4 (1.75 g, 46 mmol) was added in portions to a stirred solution of 4-bromo-5-methylbenzoic acid (10 g, 46 mmol) in THF (100 mL) at 0° C. After 15 min, H2O (50 mL) was added drop wise to the reaction which was then extracted with EtAOc (100 mL×3). The combined organic layers were washed with brine (200 mL×2), dried (Na2SO4), and concentrated under reduced pressure to yield compound 2 as a light yellow syrup (9.25 g, 46 mmol, 100% yield). 1H NMR, (400 MHz, CDCl3): δ 7.52 (d, J=8.2 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.88-7.10 (m, 1H), 4.63 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](Cl)[N:14]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)CO>[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:24]=1[NH:25][C:15]1[N:14]=[C:13]([N:10]2[CH2:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: Cc1cc(N2CC=C(c3ccccc3)CC2)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: Cc1cc(N2CC=C(c3ccccc3)CC2)nc(Nc2ccc(C(C)C)cc2Br)n1
Yield: 60.7 %

Procedure:
4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-2-chloro-6-methylpyrimidine (466 mg), 408 mg of 2-bromo-4-isopropylaniline hydrochloride and 232 mg of diisopropylethylamine were heated in 5 ml of ethylene glycol under reflux for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=6/1) to give 458 mg of 2-[N-(2-bromo-4-isopropylphenyl)amino]-4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine as an amorphous substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>ClCCl.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[C:17]([OH:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4](=[O:9])[O:3]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 72 g) in dichloromethane (1 l) was added pyridine (81 ml). Then, palmitoyl chloride (150.7 g) was added thereto at 0° C. The mixture was stirred at 0° C. for 1 hour and for additional 2 hours at ambient temperature. The reaction mixture was diluted with chloroform (1 l), poured into ice water (1 l), acidified with dilute hydrochloric acid solution, and washed with water (500 ml×3). After drying over magnesium sulfate, the solvent was evaporated under reduced pressure to give 2,2-dimethyl-5-(1-hydroxyhexadecylidene)-1,3-dioxane-4,6-dione (200 g) as an oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:9]2[CH2:10][CH2:11][C@@H:5]([C@@H:6]3[C@H:8]2[CH2:7]3)[C@@H:4]1[C:12]([O:14][CH3:15])=[O:13].C([O-])(=O)C.[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:2][C@@H:3]2[C@@H:9]3[CH2:10][CH2:11][C@@H:5]([C@@H:6]4[C@H:8]3[CH2:7]4)[C@@H:4]2[C:12]([O:14][CH3:15])=[O:13])=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H]1[C@H](N)[C@@H]2CC[C@H]1[C@H]1C[C@H]12
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@H]2CC[C@H]([C@@H]3C[C@@H]32)[C@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
rac-Methyl (1R,2R,4S,5S,6S,7R)-7-aminotricyclo[3.2.2.02,4]nonane-6-carboxylate hydrochloride (0.43 g, 1.85 mmol) was dissolved in methanol (10 mL). Sodium acetate (0.30 g, 3.70 mmol) was added followed by 4 Å powdered molecular sieves (0.40 g) and 4-fluoro-benzaldehyde (0.20 mL, 1.85 mmol). Sodium cyanoborohydride (0.23 g, 3.70 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, rac-Methyl (1R,2R,4S,5S,6S,7R)-7-{[(4-fluorophenyl)methyl]amino}tricyclo[3.2.2.02,4]nonane-6-carboxylate as a clear oil. LC-MS (ESI) calcd for C17H22FNO2 291.36, found 292.2 [M+H+].
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:24]([O:26]C)=[O:25])[C:14]4=[O:32])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:24]([OH:26])=[O:25])[C:14]4=[O:32])[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(C5CCC5)CC4)cc3c2=O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C4CCC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 1 which is concerned with the preparation of starting material methyl 3-[6-[4-(cyclobutyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate was hydrolysed with 1N NaOH to give 3-[6-[4-(cyclobutyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid; NMR Spectrum: (DMSOd6) 1.77 (m, 2H), 2.18 (s, 3H), 2.21 (m, 2H), 2.37 (m, 2H), 3.02 (m, 2H), 3.24 (m, 2H), 3.46 (m, 2H), 3.75 (m, 1H), 4.03 (m, 2H), 7.59 (m, 2H), 7.70 (m, 2H), 7.93 (s, 1H), 8.01 (d, 1H), 8.17 (s, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[O:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:7])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCBr
Yield: 94.2 %

Procedure:
A solution of 3-bromopropylamine hydrobromide (10.9 g, 49.8 mmol), BOC2O (11.4 g, 52.3 mmol) and K2CO3 (20.6 g, 149.4 mmol) in ethanol (100 ml) were stirred at room temperature overnight. The precipitated salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 11.2 g (46.9 mmol, 94%) of the desired product: 1H NMR (400 MHz, CDCl3) δ 5.07 (br, 1H), 3.31 (t, 2H, J=6.6 Hz), 3.12 (apparent br q, 2H, J=6.0 Hz), 1.92 (quintet, 2H, J=6.6 Hz), 1.30 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C1C(=O)N([Br:36])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:36][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1F
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of 2-fluoro-4-methyl-benzonitrile (1.45 g, 10.7 mmol) in CCl4 (100 mL) was added 1,1′-azobis(cyclohexanecarbonitrile) (0.240 g, 0.982 mmol) and NBS (2.19 g, 12.3 mmol). The mixture was stirred and heated at reflux overnight, and then cooled to room temperature. A solution of Na2S2O3 (5 g) in H2O (100 mL) was added, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (3×50 mL), and the extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on silica gel column (1:10 EtOAc/hexanes), affording 4-bromomethyl-2-fluoro-benzonitrile as a pale yellow oil (1.49 g, 65%). 1H NMR (CDCl3) δ 4.45 (s, 2H), 7.24-7.30 (m, 2H), 7.60 (dd, 1H, J=6.3, 8.1 Hz).
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][C:21]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl>ClCCl>[NH2:25][C:21]1([CH3:24])[CH2:20][CH2:19][CH:18]([O:17][C:8]2[C:7]3[C:6]4[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=4[S:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:23][CH2:22]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CC1(N)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (100 mg, 0.22 mmol, 1.00 equiv) in dichloromethane (5.0 mL) was added hydrochloric acid (6 N, 0.3 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The crude product (90 mg) was purified by preparative HPLC under the following conditions (Waters): column: XBridge Prep C18 OBD column: 5 um, 19*150 mm, mobile phase: water with 0.05% NH4HCO3 and CH3CN (5% CH3CN up to 16% in 2 min, hold 16% in 11 min, up to 95% in 2 min, down to 5% in 2 min); flow rate: 20 mL/min; UV detection at 254 & 220 nm. This resulted in 28.4 mg (36%) of 2-[(3R)-12-[(4-amino-4-methylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide as a white solid. MS: m/z 361 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]>C(#N)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C@:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CN1C(=O)[C@]2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21

Procedure:
4′-Bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.32 g, 8.58 mmol) was resolved on a semi-preparative chiral column (CHIRALPAK-IA, Chiral Technologies, Inc.) and eluted with 5% acetonitrile in tert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of the racemate dissolved in acetonitrile/tert-butylmethylether (1:1). (7S)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.13 g, 81%) was the second enantiomer to elute and was isolated as a crystalline colorless solid: mp 226-227° C. (acetonitrile/tert-butylmethylether); 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.23 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 1H), 6.59 (s, 1H), 6.28 (s, 1H), 5.92-5.87 (m, 2H), 4.82 (d, J=9.7 Hz, 1H), 4.67 (d, J=9.7 Hz, 1H), 3.15 (s, 3H); MS (ES+) m/z 373.8, 375.8 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Sn](C)(C)C)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F-].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:24]([O:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:18]2[CH:17]=[N:16][CH:15]=[C:14]([O:13][CH2:12][C@@H:9]3[CH2:10][CH2:11][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=2)=[CH:36][CH:35]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Ic1ccc(CCOCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([Sn](C)(C)C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2ccc(CCOCc3ccccc3)cc2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
A solution/suspension of 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)pyridine (427 mg, 1.00 mmol), 1-[2-(benzyloxy)ethyl]-4-iodobenzene (338 mg, 1.00 mmol), CsF (304 mg, 2.00 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) and CuI (19 mg, 0.10 mmol) in anhydrous DMF (5 mL) was stirred at 50° C. for 5 h under N2. The reaction mixture was cooled and concentrated under vacuum. The residue was applied onto a silica gel column, and the product was eluted with EtOAc/petroleum ether/Et3N 3:6:0.5 as the eluent to give the title compound (280 mg, 59%) as light-yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.48 (s, 1H), 8.33 (d, J=2.1 Hz, 1H), 7.55 (d, J=8.1 Hz, 2H), 7.48 (s, 1H), 7.37-7.29 (m, 7H), 4.57 (s, 3H), 4.42 (s, 1H), 4.24 (dd, J=7.2, 3.0 Hz, 1H), 3.93 (t, J=7.2 Hz, 2H), 3.75 (t, J=7.2 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 2.43-2.30 (m, 2H), 1.42 (s, 9H). LC-MS (ESI) m/z 475 (M+H+).