Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:34])[O:25][CH:26]1[CH:33]2[CH:29]([O:30][CH2:31][CH2:32]2)[O:28][CH2:27]1)[C@H:9]([OH:22])[CH2:10][NH:11]C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[NH2:11][CH2:10][C@@H:9]([OH:22])[C@@H:8]([NH:23][C:24](=[O:34])[O:25][C@@H:26]1[C@H:33]2[C@H:29]([O:30][CH2:31][CH2:32]2)[O:28][CH2:27]1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COC2OCCC12)OCc1ccccc1
Solvent: CO
Product: NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Yield: 95 %

Procedure:
A suspension of 4.0 g (8.5 mmol) of 3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-((1S,2R)-1-benzyl-3-[(benzyloxy)carbonyl]amino-2-hydroxypropyl)carbamate and 0.5 g of 5% Pd(C) in 200 mL of MeOH was subjected to hydrogenation at 45 psi. After 3.5 hours the reaction vessel was purged with nitrogen, catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to afford 2.72 g (95%) of the desired product as a white solid. NMR (DMSO-d6): 7.23-7.04 (m, 6H), 5.45 (d, 1H), 4.91-4.75 (m, 2H), 3.79 (dd, 1H), 3.68 (t, 1H), 3.53 (m, 3H), 3.21 (m, 2H), 3.01 (dd, 1H), 2.74 (q, 1H), 2.57 (dd, 1H), 2.41 (m, 1H), 1.60-1.28 (m, 3H), 1.22 (dd, 1H). MS(ESI): 337 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([O:9]C)=O)=[CH:5][N:6]=1.O.[NH3:12]>>[CH3:1][C:2]1[S:3][C:4]([C:7]([NH2:12])=[O:9])=[CH:5][N:6]=1
Reactant: COC(=O)c1cnc(C)s1
Reactant: N
Solvent: O
Product: Cc1ncc(C(N)=O)s1
Yield: 73 %

Procedure:
1.4 g Methyl 2-methylthiazol-5-carboxylate was added to 25 ml ammonia water, to carry out reaction at room temperature for 3 hr. The reaction product was cooled down, filtered, and washed with water to obtain 0.95 g a white powdery solid (73%) with mp 202-205 (C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[N:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:39]=[CH:38][C:37]([N:51]5[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])[CH2:53][CH2:52]5)=[C:36]([O:35][CH3:34])[CH:41]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 68 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (200 mg, 0.380 mmol) was coupled with tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (175 mg, 0.418 mmol) using sodium carbonate (121 mg, 1.1422 mmol) and Pd(dppf)Cl2 (14 mg, 0.019 mmol) in toluene/ethanol/water (4/4/2 mL). This afforded 190 mg (68.0% yield) after purification by column (Silica gel 60/120) using 40% ethyl acetate in hexane as eluent. MS: m/z=737.1 (M+1).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH:20]=[O:21])[CH:12]=1)=O)(C)(C)C.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[CH:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][C@@H:9]([C:22]([O:24][CH3:25])=[O:23])[NH2:8])=[CH:12]1)=[O:21]
Reactant: COC(=O)[C@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1cn(C=O)c2ccccc12
Reaction time: 15 h
Yield: 99 %

Procedure:
To methylene chloride (200 mL) solution of the compound obtained in Example 28 (8.9 g, 25.7 mmol) was added dropwise 4 mol/L of hydrogen chloride-dioxane (19 mL) at room temperature, and the mixture was allowed to stir for 15 hours. The crystals precipitated were filtered, and washed with diethyl ether, to give the captioned compound (7.2 g, 99%).
Reaction SMILES: BrC1C=C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)C([O:8]C)=NC=1.Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)=O>>[C:33]([N:28]1[CH2:26][CH2:25][C@@H:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)(=[O:8])[CH:32]=[CH2:31]
Reactant: COc1ncc(Br)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Product: C=CC(=O)N1CC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1

Procedure:
Following Example 1, but using (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (Example 1 Step 3) and reaction with acroyl chloride (Example 1 Step 6) provided the desired compound after purification: 1H NMR (300 MHz, DMSO-d6) 11.86 (br s, 1H), 8.52, (d, J=4.8 Hz, 2H), 7.64 (br s 2H), 7.28 (br s, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.50-6.70 (m, 1H), 6.13 (d, J=16.8 Hz, 1H), 6.55-6.75 (m, 2H), 4.10-4.30 (m, 1H), 3.90-4.05 (m, 1H), 3.20-3.65 (m, 3H), 1.85-2.35 (m, 2H); MS (ES) m/z 311 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])=[CH:31][CH:30]=1>>[C:33]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:42][CH:41]=1)(=[O:34])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NCc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(c1ccccc1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 96 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (272 mg, 0.64 mmol) with 4-(aminomethyl)benzophenone (prepared by following the procedure described in J. Biol. Chem. 1993, 268 (19), 14230) (270 mg, 1.3 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 17:3 and 4:1) to give 6-(4-benzoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (300 mg, 96%).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][CH2:17][O:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:35])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:28][C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:14]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCCCNC(=O)OC(C)(C)C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
A solution of [4-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (4 mg) in THF/H2O (1 mL, 1:1) was treated with LiOH (1.4 mg) at 0° C. and the reaction was stirred at room temperature for 2 h. The mixture was acidified to pH 3 with 1N HCl and purified by preparative HPLC to give the title compound (1.5 mg) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.40 (s, 1H), 8.28-8.27 (m, 1H), 8.14-8.13 (m, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H), 5.63-5.59 (m, 1H), 4.05 (t, 2H), 3.23-3.20 (m, 2H), 3.18-3.16 (m, 1H), 2.39-2.31 (m, 1H), 1.96 (t, 2H), 1.40 (s, 9H). MS calcd for (C21H26BN3O8+H-Boc)+: 360.2. MS found: (M+H-Boc)+=360.2.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+:18]>CO>[NH2:18][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: CO
Product: CCOC(=O)C=C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 200.00 g (1.041 mol) of ethyl benzoylacetate in 2,000 ml of methanol, 328.10 g (5.203 mol) of ammonium formate was added, and the resulting mixture was heated under reflux for 14 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated off under reduced pressure. To the residue, 500 ml of ethyl acetate and 400 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated, and the aqueous layer was extracted with 500 ml of ethyl acetate. The organic layers were combined, washed twice with each 400 ml of water and once with 400 ml of a brine successively and dried with sodium sulfate. The solvent was removed under reduced pressure, and the residue was then distilled to give the objective ethyl 3-amino-3-phenylacrylate (190.20 g, a colorless oil). The yield was 95.1%.
Reaction SMILES: [NH2:1][C:2]1[C:8]2=[CH:9][CH:10]=[CH:11][N:7]2[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[Cl-].[NH4+].[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21]N>C1(C)C=CC=CC=1>[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH:1][C:2]1[C:8]2=[CH:9][CH:10]=[CH:11][N:7]2[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1
Reactant: NC1=Nc2ccccc2Cn2cccc21
Reactant: COC(CN)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COC(CNC1=Nc2ccccc2Cn2cccc21)OC
Temperature: 0 °C

Procedure:
11-Amino-5H-pyrrolo[2,1-c][1,4]benzodiazepine (described by W. B. Wright et al., J. Med. Chem., 23,462 (1980), 2.00 g, 10.1 mmol) and ammonium chloride (200 mg, 19 mmol) were stirred in dry toluene (50 mL) in the presence of aminoacetaldehyde dimethylacetal (8.8 mL) under refluxing conditions for 3 hr. The precipitate which formed in the beginning redissolved to afford a brown solution. The reaction mixture was cooled in ice-water, washed with 10% (v/v) aqueous sodium hydroxide and then with brine, dried and evaporated to yield an oily residue. Crystallization of the residue from cyclohexane-hexane gave [(5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)amino]acetaldehyde dimethylacetal (2.41 g), mp 132°-132.5° C.; Anal. Calcd for C16H19N3O2 : C, 67.34% H, 6.71% N, 14.73%, Found: C, 67.11% H, 6.69% N, 14.40%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[Cl:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12](Cl)=[O:13]>O.[OH-].[Na+].C1COCC1>[Cl:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:13]
Reactant: NCCCCC(=O)O
Reactant: CC(C)CC(CCl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(CCl)C(=O)NCCCCC(=O)O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
5-Aminovaleric acid (3.2 g) is dissolved in 15 ml of water containing 1.09 g of sodium hydroxide. This is cooled to 5° C. and 2-[chloromethyl]-4-methylvaleryl chloride in 30 ml of THF is added dropwise. The pH is maintained at 8-9 by the dropwise addition of 1.09 g sodium hydroxide in 20 ml of water as needed. After stirring for about 16 hours the reaction mixture is diluted with 30 ml of water and concentrated in vacuo to remove THF. The aqueous layer is washed with ether, and acidified with 10% hydrochloric acid. Product is extracted with ethyl acetate. The ethyl acetate is dried with magnesium sulfate, filtered and concentrated in vacuo to yield 4.3 g of product. Product is purified by chromatographing on 200 g of silica using as the solvent system 500 parts ether: 10 parts methanol: 5 parts acetic acid, yielding 2.0 g of material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:48][CH:49]1[CH2:52][NH:51][CH2:50]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:51]3[CH2:52][CH:49]([OH:48])[CH2:50]3)[CH:30]=[CH:29][CH:28]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 2.0 g (4.17 mmol) of the compound from Example 1A, 1.95 g (6.26 mmol) of the compound from Example 8A, 256 mg (0.280 mmol) of tris(dibenzylideneacetone)dipalladium(0), 398 mg (0.835 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) and 2.72 g (8.35 mmol) of caesium carbonate in 20 ml of anhydrous DMF was heated to 120° C. under argon in a microwave oven (Biotage Initiator, dynamic control of the incident power) for 2.5 h. After cooling to RT, 100 ml of water were added to the reaction mixture, which was extracted three times with approx. 100 ml each time of ethyl acetate. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and finally freed of the solvent on a rotary evaporator. The remaining residue was dissolved in 40 ml of THF, and 6.3 ml (6.26 mmol) of a 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF were added. After this mixture had been stirred at RT for 1 h, it was subjected to aqueous workup in the same way as described above. The remaining residue was purified by suction filtration through 200 g of silica gel with 2:1 (3 liters)→1:1 (3 liters) cyclohexane/ethyl acetate as the eluent. After concentration and drying under a high vacuum, 1.56 g (79% of theory) of the title compound were obtained.
Reaction SMILES: Br[C@H:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH2:10])=[O:9])[CH2:4][C@H:3]1[OH:11].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([C@@H:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH2:10])=[O:9])[CH2:4][C@H:3]1[OH:11])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: NC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CC[C@@H](C(N)=O)C[C@H]1O
Yield: 57 %

Procedure:
(1R,3R,4S)-4-Bromo-3-hydroxy-cyclohexanecarboxylic amide (b) (2.31 g, 10.4 mmol) was treated with sodium azide (1.35 g, 20.8 mmol) in DMF (100 mL) at 60° C. for 15.5 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography (Silica gel, DCM:MeOH 0-10%) to give a white solid (1.09 g, 5.93 mmol, 57%).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]([OH:9])[O:3]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]([O:9][C:10](=[O:12])[CH3:11])[O:3]1
Reactant: CC1OC(O)C=CC1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1C=CC(=O)C(C)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 12.8 g quantity of 2-methyl-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran and 25 ml of acetic anhydride are reacted in the presence of 12.5 ml of pyridine with stirring at room temperature for 4 hours. After the reaction, the mixture is concentrated, the residue is poured into ice water, and the mixture is extracted with 100 ml of ether. The ethereal layer is washed with an aqueous solution of sodium carbonate and then dried over magnesium sulfate. After removing the magnesium sulfate, the ethereal layer is concentrated, and the residue is distilled at a reduced pressure of 0.4 mm Hg to give 12.6 g of 2-methyl-6-acetoxy-3-oxo-3,6-dihydro-2H-pyran as a colorless liquid fraction at 80° to 83° C in a yield of 80%.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][CH:2]=1
Reactant: COc1ccc(C=O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1

Procedure:
Namely, (R)-(+)-endo-2-norborneol (2) in tetrahydrofuran is reacted under reflux with 3-hydroxy-4-methoxybenzaldehyde in the presence of diethyl azodicarboxlate and triphenyl phosphine to obtain 3-[(2S)-exo-bicyclo[2.2.1]hepto-2-yloxy]-4-methoxybenzaldehyde (6), then via three steps (as shown in EPO 428 313 A), and the pyrimidone derivative (9) is derived.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[C:26]4[N:30](C5CCCCO5)[N:29]=[CH:28][CH:27]=4)=[O:18])[CH2:15]3)[CH2:10]2)[N:3]=1.Cl.C(O)=O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[C:26]4[NH:30][N:29]=[CH:28][CH:27]=4)=[O:18])[CH2:15]3)[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4ccnn4C4CCCCO4)C[C@@H]32)n1
Agent: Cl
Solvent: O=CO
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4ccn[nH]4)C[C@@H]32)n1
Reaction time: 1.5 h
Yield: 97 %

Procedure:
(1R,6S)-8-(4,6-Dimethylpyrimidin-2-yl)-3-({5-fluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]phenyl}carbonyl)-3,8-diazabicyclo[4.2.0]octane (8 mg, 0.017 mmol) was combined with 6 M aq. HCl (8.154 mL, 0.05 mmol) in formic acid (2.5 mL, 0.75 mmol) and stirred for 90 min. The reaction mixture was concentrated from MeON (3×12 mL), then the mixture was dissolved in NH3 MeON and concentrated to neutralize acid. The residue was dissolved in CHCl3 and purified by FCC to afford the title compound (6.7 mg, 100%). MS (ESI) mass calcd. for C22H23FN6O, 406.5; m/z found, 407.2 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)=[O:5].[CH2:18]([Mg]Br)[CH3:19]>O1CCCC1>[C:11]1([C:9]2[S:10][C:6]([C:4](=[O:5])[CH2:18][CH3:19])=[CH:7][N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1cnc(-c2ccccc2)s1
Solvent: C1CCOC1
Product: CCC(=O)c1cnc(-c2ccccc2)s1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 0.32 g (1.3 mmol) of the above-prepared 2-phenyl-thiazole-5-carboxylic acid methoxy-methyl-amide in tetrahydrofuran at room temperature was added 0.34 g (2.6 mmol) of IM ethyl magnesium bromide in tetrahydrofuran. The reaction mixture was allowed to stir for one hour. The reaction was quenched with aqueous ammonium chloride and partitioned with ethyl acetate. The organic phase was washed once with aqueous ammonium chloride, once with water, once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 1:19 ethyl acetate:hexanes to give 0.26 g of the title compound (93%). 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H) 8.0 (m, 2H) 7.49 (m, 3H) 2.98 (q, 2H) 1.27 (t, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].OO.C(OCC)C>O1CCCC1.O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:15]([OH:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Yield: 95 %

Procedure:
50.6 g of 3-(4-phenoxyphenyl)-5-phenylpentan-2-one was dissolved in 1280 ml of tetrahydrofuran, and 180 ml of a 1M tetrahydrofuran solution of tri-sec-butyllithium borohydride was added under cooling to -78° C. with stirring, followed by stirring at the same temperature for one hour. To the reaction solution, 224 ml of a 4N sodium hydroxide aqueous solution was added under cooling with ice with stirring, and then 118 ml of a 30% hydrogen peroxide aqueous solution was gradually dropwise added, followed by stirring at 0° C. for one hour. Ethyl ether and water were added to the reaction solution, followed by extraction. The organic layer was washed with a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 47.2 g (yield: 95%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([S:12]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1F
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(OC(C)C)c(F)c2)n(-c2cccc3ncccc23)n1
Temperature: 85 °C
Yield: 30.9 %

Procedure:
A mixture of 3-fluoro-4-isopropoxybenzene-1-sulfonyl chloride (0.050 g, 0.19 mmol), 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.025 g, 0.11 mmol), and DMAP (0.020 g, 0.16 mmol) in pyridine (2 mL) was heated at 85° C. for 2 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.034 mmol, 31%). 1H NMR (400 MHz, CD3OD) δ 8.85 (d, J=4.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.45-7.40 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 7.12 (dd, J=2.4, 10.4 Hz, 1H), 6.92 (t, J=8.4 Hz, 1H), 6.10 (s, 1H), 4.63 (hept, J=6.4 Hz, 1H), 2.27 (s, 3H), 1.37 (d, J=6.4 Hz, 6H); MS: (ES) m/z calculated for C22H22FN4O3S [M+H]+ 441.2. found 441.2.