Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:13]=[CH:12][C:11]3[C:10](=[O:14])[N:9](COCC[Si](C)(C)C)[CH:8]=[N:7][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[OH-].[K+]>ClCCl>[CH:1]1([C:4]2[N:13]=[CH:12][C:11]3[C:10](=[O:14])[NH:9][CH:8]=[N:7][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cnc2cc(C3CC3)ncc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cnc2cc(C3CC3)ncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 7-cyclopropyl-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one (6, 2.0 g, 6.3 mmol) in dichloromethane (10 mL) at 0° C. was added a 20% trifluoroacteic acid solution in dichloromethane (10 mL, 6.3 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. After complete deprotection as indicated by TLC the reaction mixture was concentrated, taken up in dichloromethane and concentrated. This process was repeated 2-3 times. Tetrahydrofuran (20 mL) was added to the crude residue and cooled to 0° C. 3 M potassium hydroxide solution (10 mL, 6.3 mmol) was added to the solution bringing the pH to 9-10. The suspension was stirred for 6-7 h. The reaction was concentrated, the residue was diluted with 10% methanol in dichloromethane and the organic layers were washed with 10 mL water and 10 mL of a saturated brine solution. The organic layers were separated, dried over magnesium sulfate, filtered and concentration to dryness to afford 7-cyclopropyl-3H-pyrido[4,3-d]pyrimidin-4-one (7) as a brown solid. Yield: 1.00 g, 85%; MS (ESI) m/z 188.18 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.57 (bs, 1H), 9.15 (s, 1H), 8.32 (s, 1H), 7.38 (s, 1H), 2.27 (bs, 1H), 1.03 (bs, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].[Cl:33][CH2:34][CH2:35][N:36]=[C:37]=[O:38]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:33][CH2:34][CH2:35][NH:36][C:37](=[O:38])[O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: O=C=NCCCl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)NCCCl)c3cc(Cl)ccc32)c(C)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Tolvaptan (1.0 g, 2.2 mmol) was suspended in toluene (7 ml). 2-Chloroethyl isocyanate (0.28 ml, 3.3 mmol) and 4-dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) were added thereto, and the mixture was stirred at 80° C. for 24 hours. After cooling to room temperature, the insoluble materials were filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=54:46→33:67). The purified product was concentrated under reduced pressure to obtain 1.0 g of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} (2-chloroethyl)carbamate as white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12.[OH-].[K+].ClCCl.CO>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCC(CCO)CC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(-c3cc4c(Cl)ccnc4[nH]3)cn(CCN3CCC(CCO)CC3)c2cc1OC
Yield: 64.3 %

Procedure:
But using 0.160 g of 2-[1-(2-{3-[4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxyindol-1-yl}ethyl)piperidin-4-yl]ethanol and 0.58 g of potassium hydroxide in 10 ml of methanol. After flash chromatography on a silica column [eluent: dichloromethane/methanol (80/20 by volume)], 0.078 g of 2-(1-{2-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dimethoxyindol-1-yl]ethyl}piperidin-4-yl)ethanol is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH:7]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:35][N:36]([CH3:41])[CH2:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:26]=[C:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH:7]=1)=[O:39]
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)CN(C)C)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 80 °C
Yield: 34.8 %

Procedure:
To a stirred mixture of N-(5-amino-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (200 mg, 0.45 mmol), N,N-dimethylglycine (70 mg, 0.68 mmol) and Hunig's base (365 μL, 2.1 mmol) in dimethylformamide (1 mL) was added HATU (310 mg, 0.82 mmol). The stirred mixture was heated to 80° C. for 1 h, the cooled to rt and purified by preparative reverse phase HPLC to give N-{5-[(N,N-dimethylglycyl)amino]-2-methylphenyl}-4-[(4-phenylquinazolin-2-yl)amino]benzamide (83 mg, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.71 (s, 1H), 8.18 (d, 2H), 7.99 (d, 2H), 7.85 (m, 6H), 7.65 (m, 3H), 7.45 (dq, 2H), 7.18 (d, 1H), 3.06 (s, 2H), 2.28 (s, 6H), 2.0 (s, 3H). MS (EI) for C32H30N6O2: 531.1 (MH+).
Reaction SMILES: [C:1](/[N:3]=[C:4](\OC1C=CC=CC=1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)#[N:2].C(#N)C.[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[C:1](/[N:3]=[C:4](\[N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)#[N:2]
Reactant: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Reactant: C1CCNCC1
Solvent: CC#N
Product: COC(=O)[C@H]1CN(/C(=N/C#N)N2CCCCC2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1

Procedure:
To a stirred solution of methyl (3R,4S)-1-[(Z)-(cyanoimino)(phenoxy)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (52 mg, 0.00010 mol) in acetonitrile (2.006 mL, 0.03840 mol) was added piperidine (0.200 mL, 0.00202 mol). The reaction mixture refluxed(oil bath at 85 deg). Upon completion reaction mixture concentrated in vacuum. The residue was purified by combiflash using 0-5% methanol/dichloromethane to give the product (53.3 mg, 98% in yield). MS (ESI): (M+H)+=506.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]1)=[O:22].[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[C:37]2[CH:36]=[CH:35][N:34]=[C:33]([Cl:32])[CH:38]=2)=[CH:4][C:3]=1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]1)=[O:22]
Reactant: CC(C)N1CCN(C(=O)c2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3cc2Cl)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2cc3cc(C(=O)N4CCC(F)(F)CC4)n(-c4ccnc(Cl)c4)c3cc2Cl)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [6-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 227), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (19%).
Reaction SMILES: Br[C@@:2]1([N:28]2[CH2:36][C:34]([CH:37]([O:44][CH3:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:18][C@H:6]([CH:7]([CH:9]([O:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[C@@:4]([CH:19]([O:26][CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:5])[CH2:3]1.[O-:46][CH2:47][CH3:48].[Na+].Cl>C(O)C>[CH2:47]([O:46][C@@:2]1([N:28]2[CH2:36][C:34]([CH:37]([O:44][CH3:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:18][C@H:6]([CH:7]([CH:9]([O:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[C@@:4]([CH:19]([O:26][CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:5])[CH2:3]1)[CH3:48]
Reactant: COC(c1ccccc1)C(O)[C@H]1O[C@@](Br)(N2CC(C)(C(OC)c3ccccc3)C(=O)NC2=O)C[C@@]1(O)C(OC)c1ccccc1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCO[C@]1(N2CC(C)(C(OC)c3ccccc3)C(=O)NC2=O)C[C@@](O)(C(OC)c2ccccc2)[C@@H](C(O)C(OC)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1′-bromo-3′, 5′, 5-tris(methoxybenzyl)thymidine in ethanol is added to a stirred solution of sodium ethoxide in ethanol at −10° C. The resulting reaction mixture is stirred at room temperature fro 1 h, neutralized with dilute hydrochloric acid. Ethanol is evaporated and the remaining mixture extracted with ethyl acetate. The crude is purified by chromatography to give a mixture of α and β diasteriomers.
Reaction SMILES: ClC(Cl)C([NH:5][C@H:6]([CH2:25][F:26])[C@H:7]([OH:24])[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:23])(=[N:16]C(=O)C(F)(F)F)=[O:15])=[CH:10][CH:9]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:5][C@H:6]([CH2:25][F:26])[C@@H:7]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH3:23])(=[NH:16])=[O:15])=[CH:12][CH:13]=1)[OH:24]
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=N)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of 2, 2-Dichloro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-(methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl)phenyl)-ethyl]-acetamide (212 mg, 0.468 mmol) in Methanol (20 mL) is added K2CO3 (322.9 mg, 2.34 mmol) the resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo to get crude which is purified by combi-flash chromatography using 15% MeOH in DCM as an eluent and washed with n-pentane and diethyl ether to afford title compound (80 mg). 1H-NMR (400 MHz, DMSO) δ: 1.60 (bs, 2H), 3.04 (s, 3H), 4.13-4.15 (m, 1.5H), 4.21-4.42 (m, 0.5H), 4.42-4.31 (m, 0.5H), 4.39-4.43 (m, 0.5H), 4.66 (bs, 1H), 7.55 (d, J=8.28 Hz, 2H), 7.87 (d, J=8.32 Hz, 2H). LC-MS (m/z): M+H=247.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:44])[CH3:43])=O)(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][C:9]([CH3:44])([CH3:43])[CH2:10]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNC(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Yield: 38.1 %

Procedure:
4-{6-[8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.400 g, 0.663 mmol) was dissolved in ethyl acetate (10 mL) and 6 N HCl (10 mL) and stirred at room temperature for 2 hours. The solvent was evaporated to give a yellow solid, which was dried in a vacuum oven for 5 hours at 50° C. The solid was triturated with EtOH (20 mL) and filtered to give 6-acetyl-8-cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.120 g, 38.1%). 1H NMR δ (400 MHz, DMSO-d6) 9.15 (s, 2H), 8.93 (s, 1H), 8.04 (d, J=3.2 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.64 (m, 1H), 5.78 (m, 1H), 3.31 (m, 2H), 3.24 (m, 2H), 3.18 (s, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 2.18 (m, 2H), 1.85 (m, 2H), 1.73 (m, 2H), 1.54 (m, 2H), 1.35 (s, 6H). MS (APCI) Calc'd for M+H: 476.3. Found: 476.1. Anal. Calc'd for C26H33N7O2 4.38 HCl: C, 49.16; H, 5.93; N, 15.43. Found; C, 49.55; H, 6.80; N, 14.76.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[C:20](=[O:21])[O:19][C:18]4[CH:17]=[C:16]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)[N:15]=[CH:14][C:13]=4[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[C:20](=[O:21])[O:19][C:18]4[CH:17]=[C:16]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[N:15]=[CH:14][C:13]=4[CH:12]=3)[N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2cc(-c3cc4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4oc3=O)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccn2cc(-c3cc4cnc(N5CCNCC5)cc4oc3=O)nc2c1
Reaction time: 2 h

Procedure:
To a suspension of t-butyl 4-(3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2-oxo-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate (115 mg, 0.25 mmol) in CH2Cl2 (2 mL) was added 4N HCl in dioxane (1 mL). The mixture was stirred for 2 hours, and then filtered. The solid was washed with ether and dried under nitrogen to give 3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-pyrano[3,2-c]pyridin-2-one hydrochloride quantitatively which was used in the next step without further purification. MS m/z 362.2 [M+H]+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([OH:27])=O)=[C:23]([F:31])[CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:47][CH:46]=1>CN(C=O)C.O>[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:46]=[CH:47][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54]([N:55]2[CH2:56][CH2:57][N:58]([C:25](=[O:27])[C:24]3[CH:28]=[C:29]([F:30])[C:21]([Cl:20])=[CH:22][C:23]=3[F:31])[CH2:59][CH2:60]2)=[O:61])=[CH:49][CH:50]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)c(Cl)cc2F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 4-chloro-2,5-difluoro-benzoic acid (40 mg, 0.21 mmol) in DMF (1 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was filtered then purified by column chromatography using silica gel 60-120 mesh and 60% ethyl acetate in hexane to afford 24 mg (23%) of N-biphenyl-4-yl-3-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 498.18 (M+1)+, 97.0%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.52 (m, 6H), 7.49 (t, 2H), 7.35 (t, 1H), 7.25 (t, 1H), 3.7 (m, 3H), 3.56 (d, 3H), 3.55 (d, 2H), 3.4 (m, 2H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:17]([O-])=O)[CH:13]=2)[N:8]=1.O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2cc(N)ccc2n1
Temperature: 25 °C

Procedure:
Tin(II) chloride dihydrate (60.4 g, 0.27 mol) and 2-methyl-6-nitroquinoline (8.4, 44.6 mmol) are stirred in ethanol and the mixture heated at reflux overnight. After cooling to room temperature, DI water (1.2 mL) is added and the solution made basic with sodium bicarbonate. The mixture is extracted with ethyl acetate (3×250 mL) and the combined organics dried (Na2SO4) and filtered. Solvent is evaporated to give a solid which is recrystallized from CH2Cl2 to give the title compound as crystals, 6.2 g (88%); mp187-189° C.; Anal. Calcd for C10H10 N2: C, 75.92; H, 6.37; N, 17.71. Found: C, 75.88; H, 6.35; N, 17.60.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([C:4](=[O:15])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].[I-].[CH3:18][S+](C)C>O1CCCC1>[CH3:3][C:2]([C:4]1([CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:18][O:15]1)([CH3:16])[CH3:1]
Reactant: CC(C)(C)C(=O)CCCOc1ccccc1
Reactant: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)C1(CCCOc2ccccc2)CO1
Yield: 81.2 %

Procedure:
9 g (41 mMol) of 2,2-dimethyl-6-phenoxy-hexan-3-one are added dropwise to a mixture of 5.5 g (49 mMol) of potassium tert.-butylate in 40 ml of tetrahydrofuran at room temperature, with stirring, whereupon a clear yellowish solution forms. 12.5 g (61.5 mMol) of trimethylsulphonium iodide are then added and the mixture is stirred at 20° to 25° C. for 12 hours. Thereafter, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue which remains is taken up in methylene chloride and the resulting solution is washed three times with water. After the organic phase has been dried, the solvent is stripped off. 7.8 g (81% of theory) of 2-(1,1-dimethyl-ethyl)-2-(3-phenoxypropyl)-oxirane are obtained in this manner in the form of a liquid of refractive index nD20 =1.503. ##STR13##
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>ClC(Cl)C>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Solvent: CC(Cl)Cl
Product: CCCCC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 33 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.10 g, 0.42 mmol), valeryl chloride (0.049 mL, 0.42 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-ylpentanamide (45 mg). MS (ESI) m/z 325; HPLC purity 100% at 210-370 nm, 10.8 min.; 98.4% at 250 nm, 10.8 min.; (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H28N2O+H+, 325.22744; found (ESI, [M+H]+), 325.2265.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N12CCN(CC1)CC2>C1C=CC=CC=1>[CH:17]1([NH:23][C:24]([N:14]2[C:15](=[O:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NC1CCCCC1
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)N1C(=O)C2(CCCCC2)NC12CCCCC2

Procedure:
11.1 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 6.88 parts of cyclohexyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 150 parts of dry benzene were heated at reflux for 30 hours, cooled and filtered to remove N,N'-dicyclohexyl urea. The benzene filtrate was evaporated to dryness and the residue crystallised from petroleum ether of boiling range 80°-100°C to give 2.60 parts of 14-cyclohexylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one having a melting point of 106° to 109°C and the following analysis by weight:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([C:15]([F:18])([F:17])[F:16])[CH2:13][NH:12][C:11]3=[O:19])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.CNC1CCCCC1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.C(OCC)(=O)C.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([C:15]([F:17])([F:18])[F:16])[CH2:13][N:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:11]3=[O:19])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCC(C(F)(F)F)N1c1ccc2ncsc2c1
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1N(c2cccnc2)CC(C(F)(F)F)N1c1ccc2ncsc2c1
Yield: 37.1 %

Procedure:
Using the same reaction conditions and work up as described in Example 1, step-3,1-benzothiazol-6-yl-5-trifluoromethyl-imidazolidin-2-one (I-172b: 0.1 g, 0.0004 mol) was refluxed with 3-bromo-pyridine (0.085 g, 0.0005 mol), copper iodide (0.0076 g, 0.00004 mol), N,N′-dimethyl-cyclohexane-1,2-diamine (0.017 g, 0.00012 mol), potassium phosphate (0.22 g, 0.0012 mol) and 1,4-dioxane (20 mL) at 120° C. for 12 hours to afford the crude product. The reaction was monitored by TLC (100% ethyl acetate). Purification by column chromatography on silica gel (2% methanol in DCM) afforded 54 mg of the product (45.2% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C@H:20]12[CH2:26][C@H:23]([NH:24][CH2:25]1)[CH2:22][N:21]2[C:27]([CH3:31])([CH3:30])[CH2:28][OH:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:24]3[CH2:25][C@@H:20]4[CH2:26][C@H:23]3[CH2:22][N:21]4[C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: CC(C)(CO)N1C[C@@H]2C[C@H]1CN2
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2C[C@@H]3C[C@H]2CN3C(C)(C)CO)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 18 h
Yield: 13.8 %

Procedure:
A solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (235 mg, 0.83 mmol), (2-(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl-2-methylpropan-1-ol (168 mg, 0.99 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (10 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (265 mg, 1.25 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 90:10) to afford the title compound as a tan solid (50 mg, 14%). LCMS (Method H): RT=2.39 min, M+H+=436.