Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([O:32][CH3:37])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:33][CH:34]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)C(CC(O)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(CC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1)c1ccccc1
Yield: 84.1 %

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-2-phenylethyl)piperazine (0.051 g, 0.11 mmol) in anhydrous ether (5 mL) was added sodium hydride (0.006 g, 0.15 mmol). The resultant mixture was stirred at ambient temperature for 30 minutes, then methyl iodide (0.016 g, 0.11 mmol) was added. Once thin layer chromatography analysis showed complete consumption of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-2-phenylethyl)piperazine had occurred, the mixture was poured into water and extracted with two portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford 0.046 g of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-methoxy-2-phenylethyl)piperazine as a yellow oil: NMR (CDCl3) 7.3 (m, 9), 7.0 (m, 2), 6.9 (m, 2), 4.8 (m, 3), 4.2 (m, 2), 3.9-3.2 (m, 5), 3.1 (d, 2), 3.0 (s, 1), 2.9 (s, 1), 2.6 (m, 1), 2.4 (m, 1), 1.9 (m, 1) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([C:45](Cl)=[O:46])[CH2:41][CH2:40]1>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:45]([N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)=[O:46])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)N5CCN(C)CC5)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with 4-methylpiperazine-1-carbonyl chloride to give the title compound. LC/MS (M+H)+: 661. Ret. time: 1.46 min. (Condition G); analytical HPLC Ret. time: 6.16 min (Condition H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Cl[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C)C=O>[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH2:21][C:20]([CH3:22])=[CH2:19])[CH:11]=1)(=[O:15])[CH3:14]
Reactant: C=C(C)CCl
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(NC(C)=O)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 104.6 parts of methyl 2-hydroxy-4-(acetylamino)benzoate in 470 parts of N,N-dimethylformamide were added portionwise 24 parts of a dispersion of sodium hydride in mineral oil (50%) under a nitrogen atmosphere. After stirring for 1 hour at room temperature, there was added a solution of 55.2 parts of 3-chloro-2-methyl-1-propene in 47 parts of N,N-dimethylformamide. Stirring was continued for 3 days at 50° C. The reaction mixture was evaporated and the residue was dissolved in dichloromethane. This solution was washed with water, sodium hydroxide 10% and water and was then dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 65.8 parts (50.0%) of methyl 4-(acetylamino)-2-[(2-methyl-2-propenyl)oxy]benzoate (interm. 15).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[N:20]1[C:21]([C:29](O)=[O:30])=[CH:22][N:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=12.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:21]3[N:20]=[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][N:23]4[CH:22]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1cn2ccncc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1cn2ccncc2n1

Procedure:
Following the method described in Example 34(d), the title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.34 g, 1.22 mmol), imidazo[1,2-a]pyrazine-2-carboxylic acid (0.2 g, 1.22 mmol), HOBt (0.25 g, 1.84 mmol), DIPEA (0.64 mL, 3.68 mmol) and EDCI (0.35 g, 1.84 mmol) using 10 mL of DMF as solvent. Yield 0.26 g. 1H NMR (400 MHz; MeOD): δ 1.30 (d, 3H), 4.44 (m, 2H), 4.58 (m, 1H), 6.77 (dd, 1H), 7.59 (dd, 1H), 7.78 (d, 1H), 7.90 (d, 1H), 8.14 (dd, 1H), 8.36 (d, 1H), 8.49 (dd, 1H), 9.06 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:11][C:12]1[CH:17]=[C:16]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cccc(N)c1
Temperature: 80 °C
Yield: 97.8 %

Procedure:
A mixture of 2-bromobenzonitrile (9.1 g, 50 mmol), 3-aminobenzeneboronic acid monohydrate (11.6 g, 75 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) in 1,2-dimethoxyethane (50 ml) and 2 M aqueous sodium carbonate (25 ml) was heated at 80° C. for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was washed with brine (400 ml), dried (Na2SO4), and evaporated in vacuo. Purification of the residue by flash chromatography (silica gel, 0-25% EtOAc/isohexane) gave 9.5 g (98%) of 3′-aminobiphenyl-2-carbonitrile as a colourless oil that solidified on standing to afford a white solid: 1H NMR (400 MHz, CDCl3) δ 3.79 (2H, br), 6.75 (1H, ddd, J 8, 3, 1 Hz), 6.84 (1H, dd, J 3, 3 Hz), 6.92 (1H, dd, J δ, 3 Hz), 7.25 (1H, dd, J 8, 8 Hz), 7.40 (1H, ddd, J 8, 8, 1 Hz), 7.50 (1H, dd, J 8, 1 Hz), 7.62 (1H, ddd, J 8, 8, 1 Hz), 7.73 (1H, dd, J 8, 1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][O:5][CH2:6]Cl.Cl.[Cl:13][C:14]1[CH:15]=[N:16][C:17](=[O:20])[NH:18][CH:19]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][N:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[N:16][C:17]1=[O:20]
Reactant: Cc1ccccc1COCCl
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1COCn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of chloromethyl 2-methylbenzyl ether (see Preparation 3a and 3b) (10 mmol) in dichloromethane (20 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and triethylamine (20 mmol) in dichloromethane (80 ml). The reaction mixture was stirred for 2 hours at room temperature. It was then washed with water and the dried (MgSO4) solution evaporated to yield a crude mixture (2.55 g, 96%) which was purified by trituration with ether. The yield of the title compound was 1.33 g (50%), m.p. 88° C. 1H NMR (CDCl3): δ2.26 (Me), 4.63 (CH2 -Ph), 5.30 (CH2O), 7.00 (Ph), 7.60 and 8.37 (H-4, H-6, J 4 Hz). IR(KBr): 1660 cm-1 (CO).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][CH:18]=[C:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.C1C[O:54][CH2:53]C1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH:53]=[O:54])=[C:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2scc(COCC[Si](C)(C)C)c21
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C=O)c(COCC[Si](C)(C)C)c21
Temperature: -78 °C

Procedure:
To a cold (−78° C.), stirred mixture of 2.03 g of N-(4-chlorobenzyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 50 mL of dry TBF is added via cannula a solution of LDA, prepared as usual in 25 mL of dry THF from 2.5 mL of diisopropylamine and 5.3 mL of a 2.5 M solution of butyllithium in hexanes. The resulting deeply colored solution is stirred for 5 min at −78° C., then 1.7 mL of dry DMF is added, causing the mixture to solidify. The mixture is allowed to warm to 0° C. whereupon it becomes fluid, and is quenched with 50 mL of 1N HCl. Aqueous workup (CH2Cl2, dil. HCl) followed by flash chromatography on silica gel using 30-40% EtOAc in CH2Cl2 affords 1.56 g of the title compound as a yellow solid. Recrystallization from EtOAc provides pale yellow crystals.
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Br:13])[CH:12]=1)[C:8]#[N:9]>CN1C(=O)N(C)CCC1.O>[Br:13][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:2][CH3:1])[CH:12]=1)[C:8]#[N:9]
Reactant: C[O-]
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: COc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Sodium methoxide (2.02 g) was added to a stirred solution of 3-fluoro-5-bromobenzonitrile (5.0 g) in DMPU (20 ml) and stirred at RT for 2 h. The reaction was diluted with water and the resulting solid formed was filtered and washed with water, then dried in vacuo to give the subtitle compound (5.10 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)([O-])=O.NC1C=CC=C[C:21]=1[C:26]1[O:27]C2C=CC=CC=2N=1>C(Cl)Cl.C(O)C.O=[Pt]=O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][C:26](=[O:27])[CH3:21]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2ccccc2o1
Reactant: Nc1ccccc1-c1nc2ccccc2o1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)Nc1ccccc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound was prepared in a multistep synthesis employing Scheme 3, as described: A suspension of 2-aminophenol (5.0 g, 45.81 mmol) and 2-nitrobenzaldehyde (6.92 g, 45.81 mmol) in cyclohexane (200 mL) was heated to reflux using a Dean-Stark apparatus to remove water for 5 h. The reaction mixture was concentrated in vacuo to yield bright yellow crystals of the corresponding imine (10.71 g, 97% yield). To a solution of this imine (7.88 g, 32.56 mmol) in CH2Cl2 (200 mL) was added Ag2O (9.05 g, 39.07 mmol) and the reaction mixture was allowed to stir at RT overnight. The solvent was removed in vacuo to yield a solid shown to be the 2-(2-nitrophenyl) benzoxazole. This product was then suspended in ethanol (200 mL) with PtO2 (0.3 g) and charged with H2 (60 psi). The reaction mixture was allowed to shake on a Parr apparatus for 3 h. This was filtered through celite and the filtrate was removed in vacuo to yield a yellow solid. 1H NMR showed this to be the desired 2-(2-aminophenyl) benzoxazole, 3.85 g. This was acetylated according to General Procedure A and purified by recrystallization from cyclohexane/ethyl acetate, m.p. 125°-128° C.; 1H NMR (300 MHz, DMSO-d6) δ11.48 (s, 1H), 8.54 (d, J=9 Hz, 1H), 8.13 (dd, J=1.5, 9 Hz, 1H), 7.80-7.75 (m, 2H), 7.57 (m, 1H), 7.45 (m, 2H), 7.25 (t, J=9 Hz, 1H), 2.23 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ5 168.79, 161.46, 148.92, 140.39, 138.59, 132.89, 128.62, 126.18, 125.28, 123.37, 120.29, 119.83, 113.05, 111.07, 25.15; IR (KBr) 3270, 1685, 1540, 1240, 750 cm-1 ; MS (DCI) m/e MH+ =253; Analysis calc' d for C15H12N2O2 : C, 71.42; H, 4.79; N, 11.10; found: C, 71.24; H, 5.14;N, 10.76.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[N:23][C:24](Cl)=[C:19]4[CH:18]=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].[C:29](=O)([O-])[O-:30].[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[N:23][C:24]([O:30][CH3:29])=[C:19]4[CH:18]=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(N2CCN(C(=O)Cn3ncc4c(Cl)ncnc43)CC2)ccc1Cl
Agent: [K+]
Solvent: CO
Product: COc1cc(N2CCN(C(=O)Cn3ncc4c(OC)ncnc43)CC2)ccc1Cl

Procedure:
To a solution of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-pyrazolo[3,4-d]pyrimidine-1-yl)-ethanone (0.024 mmol, 1 eq.) in 1 mL of MeOH was added solid potassium carbonate (excess), the resultant mixture was heated at 70° C. for 30 minutes, then filtered and dried under vacuum. The crude product was purified by HPLC to provide the desired product as a white powder: 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.07 (s, 1H), 7.22 (d, 1H), 6.50 (d, 1H), 6.44 (dd, 1H), 5.29 (s, 2H), 3.90 (s, 3H), 3.81 (m, 4H), 3.19 (m, 4H), 2.25 (s, 3H). LCMS observed for (M+H)+: 418.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[C:32]([N:36]=[C:37]=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[C:32]([NH:36][C:37]([NH:29][C:28]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:13][C:12]=2[N:27]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N=C=O
Reactant: Nc1nc2nc(NCCCN3CCOCC3)ncc2cc1-c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(NCCCN3CCOCC3)ncc2cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 6-(2,6-dichlorophenyl)-N2 -(3-morpholin-4-yl-propyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 58 in DMF (15 mL) was added one equivalent of 60% sodium hydride suspension (0.92 g). After stirring for approximately 1 hour at room temperature, one equivalent of tert-butyl isocyanate (0.230 g) was added, and the reaction was monitored by thin layer chromatography. After approximately 4 hours, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous layer was washed several times with ethyl acetate. The ethyl acetate layers were combined, dried with magnesium sulfate, and concentrated in vacuo. Chromatography of the residue on silica gel using ethyl acetate followed by ethyl acetate:ethanol:triethylamine (18:2:1) gave 0.98 g of the title compound 1-tert-butyl-3-[6-(2,6-dichlorophenyl)-2-(3-morpholin-4-yl-propylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea, CIMS (1% NH3 in CH4): 532=M+ +H, 531=M+,433, 84 (Base); mp 236°-240° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=N.[ClH:22].N([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:1][C:2]([CH3:21])([CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][O:4][N:5]=[C:6]([Cl:22])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(CONC(=N)c1cccnc1)CN1CCCCC1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CON=C(Cl)c1cccnc1)CN1CCCCC1
Reaction time: 2 h

Procedure:
To a solution containing 2.23 g (7.63 mmoles) of N-(2,2-dimethyl-3-piperidinopropoxy)-3-pyridinecarboxamidine in 30 ml of a 1:1 mixture of concentrated hydrochloric acid and water, 2.63 g (38.2 mmoles) of sodium nitrite dissolved in 10 ml of water are dropwise added at 0° C. The reaction mixture is stirred at the same temperature for an additional 2 hours, then the pH value is adjusted to 12 by adding 2N sodium hydroxide solution, and the mixture is extracted twice with 30 ml of chloroform each. The organic phase is washed with 30 ml of water, dried over sodium sulfate, filtered and evaporated. The oily residue (1.83 g) is purified by column chromatography to give the title compound as a pale yellow oil in a yield of 1.62 g (68.5%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:4][CH2:3]1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.P(=O)(O)(O)O.N>C(O)(=O)C>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]3=[O:20])[CH2:4][CH2:3]2)=[CH:23]1
Reactant: O=C1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Reactant: Cn1ccc2ccccc21
Agent: N
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: Cn1cc(C2CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)c2ccccc21
Reaction time: 144 h

Procedure:
A mixture consisting of 2.7 gm of N-[3-(4-oxo-piperidino)-propyl]-benzimidazolone, 1.3 gm of 1-methylindole, 40 ml of acetic acid and 10 ml of 2 N phosphoric acid was allowed to stand at 20° C. for 6 days. Thereafter, the reaction mixture was poured into a mixture of ice and ammonia, the aqueous mixture was extracted with ethyl acetate, and the extract solution was dried and evaporated in vacuo to dryness. The residue was purified by chromatography on silica, using methylene chloride/methanol/ammonia=90/9/1 as the eluant. The main fraction was hydrogenated without characterization as described in Example 1, and the end product was crystallized from ethanol, yielding 2.4 gm (62% of theory) of the compound of the formula ##STR14## having a melting point of 180° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[C:4]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[C:4]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1cc(O)ccc1-c1cn2ccccc2n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CN(c1cc(O)ccc1-c1cn2ccccc2n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.1 g (3.6 mmol) of 2-(4-Hydroxy-2-methylsulphonamido-phenyl)-imidazo[1,2-a]pyridine are dissolved in 10 ml of dimethylsulphoxide, then 0.6 g (4.3 mmol) of potassium carbonate and 1.1 ml (18 mmol) of methyliodide are added. The mixture is stirred at ambient temperature for one hour. It is poured onto about 100 ml of ice water and the precipitate is suction filtered. It is then washed with water.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][C:11]3=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.O>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][CH:11]3[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2c1cccc2-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCc2c(-c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To a stirred solution of 20.8 g (0.10 mole) of 4-phenyl-1-indanone in 150 ml of ethanol was added portionwise 2.0 g (0.06 mole) of sodium borohydride. During the addition the reaction temperature rose to 33° C. Upon complete addition the reaction mixture was allowed to cool to ambient temperature and was stirred for 16 hours. The reaction mixture was mixed in water and concentrated under reduced pressure. A precipitate, which developed during concentration of the aqueous solution, was collected, dried, then recrystallized from toluene-hexane to give 17.3 g of 4-phenyl-1-indanol; m.p. 80.5°-81.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([NH2:29])[CH2:26][CH2:25][N:24]1[C:30](=[O:45])[C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([C:56](O)=[O:57])=[CH:48][CH:47]=1.C(N(CC)CC)C>C(Cl)Cl>[F:43][C:41]([F:44])([F:42])[C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=1)[C:30]([N:24]1[CH2:25][CH2:26][C@H:27]([NH:29][C:56]([C:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:46]=[CH:47][CH:48]=2)=[O:57])[CH2:28][C@H:23]1[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:45]
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.95 g (11.6 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride are added at 0° C. to a solution of 4.16 g (9.67 mmol) of (2R,4S)-2-benzyl-1-(3,5-bis-trifluoromethyl-benzoyl)-4-piperidineamine [EP 532 456 A1, Example 38 f], 1.84 g (10.6 mmol) of quinoline4-carboxylic acid and 3 ml (21.3 mmol) of triethylamine in 30 ml of methylene chloride and the ice bath is removed after 10 minutes. The reaction mixture is stirred for 4 hours at room temperature and then diluted with methylene chloride. The organic phase is extracted with aqueous 10% citric acid and with 1 N potassium carbonate solution, washed with brine, dried over magnesium sulfate and concentrated to dryness by evaporation. The crude product is chromatographed on silica gel with methylene chloride/acetone (7:3). The title compound is crystallised from methylene chloride/ether/hexane in the form of white crystals. M.p.: 187° C.; TLC: methylene chloride/acetone (7:3) Rf =0.48, FD-MS: M+ =585; [alpha]D=+9.9 (c=1, methylene chloride); analysis: calc.: C=63.59%, H=4.30%, N=7.18%, F=19.47%, found: C=63.50%, H=4.40%, N=7.16%, F=19.45%. ##STR15##