Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:45]
Reactant: Cn1ncc(N)c1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1NCC1CCNCC1
Yield: 7.4 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 4-((4-amino-1-methyl-1H-pyrazol-5-ylamino)methyl)piperidine-1-carboxylate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid and HATU were reacted to give 105 as a white solid (4.4 mg, 7.4%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.36 (s, 1H), 7.67-7.36 (m, 3H), 7.27 (t, J=8.6, 2H), 4.88 (t, J=6.5, 1H), 3.63-3.55 (m, 4H), 3.01 (d, J=12.2, 2H), 2.80 (t, J=6.5, 2H), 1.76 (d, J=11.1, 2H), 1.55 (s, 1H), 1.24-1.01 (m, 2H). ESIMS m/z=448.1 (M+1)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC3C=CC(OC)=CC=3)[C:7]=2[C:22]2[CH:23]=[C:24]([CH:33]3[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]3)[C:25]3[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=3[N:32]=2)[CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1>[ClH:46].[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:7]=2[C:22]2[CH:23]=[C:24]([CH:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)[C:25]3[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=3[N:32]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3c(n2)NC(=O)OC3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3c(O)cccc3OCC3CC3)cc(C3CCCNC3)c2CO1
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of tert-butyl 3-(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl) oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1-piperidine-carboxylate (2.0 g, 3.248 mmol) in dioxane (15 mL) was added 4N HCl in dioxane (30 mL) at room temperature. The stirring was continued for 3 hrs. After the solvent was removed by evaporation, the resulting solid was triturated with acetonitrile, collected by filtration, and washed with acetonitrile. The solid was dried under reduced pressure to give 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride as a white solid (0.865 g, yield; 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32](O)=[O:33])=[N:27]1.S(Cl)(Cl)=O>CN(C)C=O.CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:32]([C:28]5[C:29]([CH3:31])=[CH:30][N:26]([CH3:25])[N:27]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cn(C)nc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1nn(C)cc1C
Yield: 46.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (323 mg, 1.0 mmol), 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (154 mg, 1.1 mmol) tetrahydrofuran (2.0 mL), N,N-dimethylformamide (1 drop), thionyl chloride (0.08 mL, 1.1 mmol) and N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 203, the title compound (208 mg, 47%) was obtained as pale-yellow crystals.
Reaction SMILES: [CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:3])[CH3:2].[CH3:46][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:46])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:2])[CH3:3]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cccc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3cccc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 150 mg (0.25 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-(3-naphthalen-1-ylmethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl) acetamide, prepared as in Example 34, in 5 mL of DMF at 0° C. is added 0.45 mL (0.45 mmol, 1.8 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 28 μL (0.45 mmol, 1.8 equiv) of methyl iodide is added. The resulting solution is stirred 3 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is then poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 3/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 120 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.93-7.86 (m, 2H), 7.77 (d, 1H, J=8.0), 7.60-7.06 (m, 16H), 6.89 (dd, 1H, J=0.8, 8.1), 4.88 (m, 1H), 4.34 (s, br, 2H), 3.81 (s, 3H), 3.20 (d, 1H, J=14.7), 3.00 (d, 1H, J=14.7), 1.01 (m, 9H); low resolution MS (FAB)m/e 612 (MH+), 611 (M+), 447.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([CH2:10][CH3:11])([CH2:8][OH:9])[CH2:4][O:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClCCl.CCOCC>[CH3:1][C:2]1([CH3:12])[O:3][CH2:4][C:5]([CH2:10][CH3:11])([CH:8]=[O:9])[CH2:6][O:7]1
Reactant: CCC1(CO)COC(C)(C)OC1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC1(C=O)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
2,2-Dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane (33 g.) was added to a stirred suspension of pyridinium chlorochromate (122.6 g) and anhydrous sodium acetate (7.8 g.) in dry dichloromethane (200 ml.), at 0°, under a current of nitrogen. The mixture was stirred at room temperature for six hours. The mixture was diluted with dry ether (500 ml) and the organic solution was decanted off. The oily residue was treated with ether and the combined extracts were evaporated in vacuo. The residue was purified by chromatography on silica, eluting with ether: hexane 1:3. 2,2-Dimethyl-5-ethyl-5-formyl-1,3-dioxane (30 g.) was obtained as a colourless oil.
Reaction SMILES: C[Al](C)C.[C:5]([C:9]1[CH:13]=[C:12]([NH2:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:7])[CH3:6].[O:21]=[C:22]1[NH:27][C:26]2[N:28]=[CH:29][CH:30]=[C:31]([O:32][C:33]3[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=3)[C:36](OC)=[O:37])[C:25]=2[N:24]=[CH:23]1>C1COCC1>[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:36](=[O:37])[C:35]2[CH:40]=[CH:41][CH:42]=[C:33]([O:32][C:31]3[C:25]4[N:24]=[CH:23][C:22](=[O:21])[NH:27][C:26]=4[N:28]=[CH:29][CH:30]=3)[CH:34]=2)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: COC(=O)c1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Method H1: A solution of AlMe3 (solution in toluene 2M, 0.85 mL, 1.68 mmol) was added dropwise to a cooled (0 C) solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (362 mg, 1.68 mmol) in THF (5.0 mL). When the addition was complete, the mixture was allowed to warm to room temperature and stirring was continued for 30 minutes. Then methyl 3-(3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)benzoate (100 mg, 0.336 mmol) was added and the mixture was heated under reflux for 19 h. The mixture was cooled to room temperature and carefully quenched with 5% aq HCl (3.0 mL). After evaporation of solvent, the residue was retaken in CH2Cl2, washed with saturated solution of NaHCO3 and dried over MgSO4 and evaporated under vacuum. The obtained residue was chromatographed (eluent: CH2Cl2/EtOAc: 2/1 towards 1/3) and the title compound was obtained as a slightly yellow solid (29 mg, 18%).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[N:4]=1)[NH2:2].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[F:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]2[N:4]3[C:5]4[C:10]([CH:11]=[CH:12][C:3]3=[N:1][N:2]=2)=[CH:9][C:8]([S:13][C:14]2[CH:15]=[C:16]([C:20]3([C:26]#[N:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=4)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N#CC1(c2cccc(Sc3ccc4nc(NN)ccc4c3)c2)CCOCC1
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5nnc(-c6ccc(F)cc6)n54)c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5i (203 mg, 0.54 mmol) was suspended in CH2Cl2. 4-Fluorobenzaldehyde (0.07 mL, 0.65 mmol) was added, and the reaction was stirred at room temperature for 4 hours. Iodobenzene diacetate (176 mg, 0.54 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction was adsorbed onto silica gel and concentrated, and then purified by silica gel chromatography (20-100% EtOAc in hexanes, followed by 0-10% MeOH in EtOAc) to give the desired product, 5j.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][C:18]2[CH:19]=[C:20]([NH2:25])[CH:21]=[CH:22][C:23]=2[CH3:24])[CH:3]=1.[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.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=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][C:18]2[CH:19]=[C:20]([NH:25][C:35](=[O:36])[C:34]3[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=[C:32]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:33]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])[CH:3]=1
Reactant: Cc1ccc(N)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Reactant: O=C(O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N3-[1-(6-amino-pyrimidin-4-yl)-1H-benzoimidazol-2-yl]-4-methyl-benzene-1,3-diamine (10.0 mg, 0.030 mmol), 3-morpholin-4-yl-5-trifluoromethyl-benzoic acid (10 mg, 0.036 mmol), and DIEA (21 μL, 0.12 mmol) in DMF (2 mL) is added HATU (13 mg, 0.033 m mol). After stirring for 1 hour at room temperature, the solvent is removed under vacuum. The residue is dissolved in DMSO (1 mL). The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][C:22]1[CH:26]=[C:25]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[NH:24][C:23]=1[CH:35]=O>N1CCCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:23]4[NH:24][C:25]([C:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)=[O:28])=[CH:26][C:22]=4[CH3:21])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=O
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)N(C)c2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 90 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (116 mg, 0.4 mmol), 3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (130 mg) and piperidine (1 drop) in ethanol (2 mL) was stirred at 90° C. for 2 hours. The reaction was diluted with water and the precipitate was collected by vacuum filtration, washed with water, ethyl acetate and hexane and dried to give 141 mg (74%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.42 (br s, 1H, NH), 9.29 (br s, 1H), 8.38 (s, 1H), 7.72 (m, 1H), 7.34-7.41 (m, 3H), 6.6 (s, 1H), 3.67 (m, 4H, 2×CH2), 3.65 (m, 4H, 2×CH2), 3.29 (s, 3H, CH3), 2.20 (s, 3H, CH3). MS 497 [M++1].
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25](N(OC)C)=[O:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:37][Mg]Br>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25](=[O:26])[CH3:37])=[CH:14][CH:13]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
Tert-butyl(2-isobutyl-6-{[methoxy(methyl)amino]carbonyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.175 g, 0.355 mmol) was dissolved in tetrahydrofuran (5 mL) and a solution (0.15 mL, 0.43 mmol) of 3 M methyl magnesium bromide in diethyl ether was added dropwise under ice-cooling. This mixture was stirred at room temperature for 1 h and quenched with saturated aqueous ammonium chloride solution (5 mL). The whole was extracted with ethyl acetate (10 mL), and the organic layer was washed once each with 0.1 M aqueous citric acid solution (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2 (v/v)) to give tert-butyl(6-acetyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.132 g, 83%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].COC(OC)N(C)C.CN(C)C=O>>[N+:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:3]2[C:2]=1[CH:1]=[CH:7][O:6][C:4]2=[O:5])([O-:14])=[O:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: O=c1occc2c([N+](=O)[O-])cccc12
Temperature: 115 °C
Reaction time: 17 h
Yield: 94.2 %

Procedure:
Methyl 2-methyl-3-nitrobenzoate (5 g, 0.02 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine (10 mL, 0.07 mol) were dissolved in N,N-dimethylformamide (30 mL, 0.4 mol). The mixture was stirred at 115° C. for 17 hours. The volatiles were removed on a rotavapor. The residue was dissolved in ethylacetate (400 mL) and then silica gel (400 g) was added. The mixture was stirred at room temperature for 3 hours. Filtered, rinsed with ethylacetate (400 mL×3). Combined filtrates were concentrated to dryness to get a brown solid (3.6 g). MS m/z=192.0 (M+1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[CH3:19][C@H:20]1[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][O:21]1.[Cl-].[NH4+]>C1COCC1>[Cl:13][C:14]1[S:15][C:16]([C@@:24]2([OH:26])[CH2:23][CH2:22][O:21][C@@H:20]([CH3:19])[CH2:25]2)=[CH:17][N:18]=1
Reactant: C[C@H]1CC(=O)CCO1
Reactant: Clc1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@H]1C[C@@](O)(c2cnc(Cl)s2)CCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
n-Butyl-lithium (2.5M in hexane, 57.5 ml) was dropwise added during 30 minutes to a solution of di-isopropylamine (19.3 ml) in THF (180 ml) which had been cooled to -78° C. The mixture was stirred at -78° C. for 1 hour. The reaction vessel was shielded from light and 2-chlorothiazole (15.0 g) was added dropwise during 20 minutes, whilst keeping the temperature of the reaction mixture below -70° C. The mixture was stirred at -78° C. for 1.5 hours. (2S)-2-Methyltetrahydropyran-4-one (12.9 g) was added during 20 minutes. The mixture was stirred and allowed to warm briefly to -25° C. to obtain a homogeneous solution. The mixture was recooled to -70° C. and stirred at that temperature for 1 hour. A 5% aqueous solution of ammonium chloride was added and the mixture was extracted with diethyl ether. The organic solution was washed with brine, dried (MgSO4) and evaporated. There was thus obtained a mixture (29.4 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 1:4. The mixture so obtained was dissolved in diethyl ether (250 ml) and the solution was cooled to 0° C. A concentrated (25% v/v) aqueous solution of sulphuric acid was added and the mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (750 ml) and neutralised to pH3 by the addition of sodium bicarbonate. The organic solution was washed with brine, dried (MgSO4) and evaporated to give a mixture (26 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 9:1. The material was purified by column chromatography using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran (21 g, 79%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[OH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[H-].[Na+]>CN(C)C=O>[F:8][C:4]1[N:3]=[C:2]([O:9][CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2cccc(F)n2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 2,6-difluoropyridine (5 g, 43.4 mmol) and 4-(hydroxymethyl)benzonitrile (8.67 g, 65.1 mmol) was added sodium hydride (2.56 g, 65.1 mmol, 60% in oil) at room temperature. This mixture was stirred for 4 hours at 70° C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=10:1-4:1) to obtain the title compound (5.99 g, 61%).
Reaction SMILES: C([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=O)C.S(Cl)(Cl)=O.[NH2:21][CH:22]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]1>>[NH2:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:21][CH:22]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: CN1CCC(N)C1
Solvent: O=S(Cl)Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(C)C1
Reaction time: 1 h

Procedure:
A suspension of 5.3 g. (0.022 mole) of 4-acetamido-5-chloro-2-methoxybenzoic acid in 30 ml. of thionyl chloride was refluxed for two hours and then concentrated. To the concentrate was added 100 ml. of chloroform and the solution was again concentrated. The residue was again dissolved in chloroform and added at a rapid drop to a chloroform solution containing 2.4 g. (0.024 mole) of 3-amino-1-methylpyrrolidine. The solution was stirred for one hour and concentrated. The residue was dissolved in 100 ml. of 4N hydrochloric acid and the solution was refluxed for 10 minutes, cooled in an ice bath and basified with sodium hydroxide. The mixture was extracted with chloroform and the extract dried and concentrated. The crystalline residue was recrystallized from isopropyl ether-isopropyl alcohol followed by another recrystallization from ethyl acetate. The yield of product was 1.4 g. (22 %); m.p. 185°-187°C.
Reaction SMILES: FC(F)(F)C(O)=O.[O-:8][C:9]#[N:10].[Na+].NN.[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([N:25]([CH2:27][C:28]([O:30]C)=O)[NH2:26])[CH:22]=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:27][C:28](=[O:30])[NH:10][C:9](=[O:8])[NH:26]2)[CH:22]=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH3:17]
Reactant: N#C[O-]
Reactant: CCCCOc1cccc(N(N)CC(=O)OC)c1
Agent: NN
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCOc1cccc(N2CC(=O)NC(=O)N2)c1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.2 ml, 15.5 mmol) was added to a suspension of sodium cyanate (1.17 g, 18.0 mmol) and hydrazine (Intermediate 47 1.30 g, 5.15 mmol) in toluene (17 ml) at room temperature and stirred for 2 h. The reaction was quenched with sodium bicarbonate solution, extracted with ethyl acetate and washed with sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated to afford the urea intermediate as a brown oil. A portion of this crude urea (0.65 g, 2.2 mmol) was taken up in methanol (10 ml) and treated with sodium methoxide (0.48 g, 8.8 mmol) at room temperature for 2 h. The reaction was quenched (pH 6.5 buffer), extracted with ethyl acetate, washed with water followed by brine, dried (Na2SO4) and concentrated to afford a red oil which was triturated with ether to afford a pale brown solid (105 mg, 18%), m.p. 100°-105°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][CH:36]([CH3:38])[CH3:37])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(C)COS(=O)(=O)C(F)(F)F
Product: COc1cn(C(CC(C)C)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
416 mg (1.00 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 1.20 ml (1.20 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 309 mg (1.50 mmol, 1.5 eq.) of isobutyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 370 mg (75% of theory)