Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:31]([C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1)[CH3:32]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:12]([CH:31]([C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])=[CH:35][CH:34]=3)[CH3:32])[N:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Cl)cc(-c2cc(-c3ccc4nccnc4c3)n[nH]2)c1
Reactant: CC(Br)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(C(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from step E (330 mg, 0.97 mmol) in 8 mL of anhydrous DMF was added Cs2CO3 (473 mg, 1.45 mmol) followed by tert-butyl 4-(1-bromoethyl)benzoate (331 mg, 1.16 mmol). The reaction was stirred at room temperature overnight and then diluted with water. The aqueous layer was then extracted with EtOAc (3×) and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography (20% EtOAc/Hexanes) to give the product as a yellow oil. 1H NMR (CDCl3, 500 MHz): 1.60 (s, 9H), 2.02 (d, J=7.1 Hz, 3H), 5.67 (q, J=7.1 Hz, 1H), 6.78 (s, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.34 (t, J=1.8 Hz, 1H), 7.68 (dd, J=8.7, 1.9 Hz, 1H), 7.83 (d, J=1.8, 2H), 7.95 (d, J=8.2 Hz, 2H), 8.10 (d, J=1.9, 1H), 8.18 (d, J=8.7, 1H), 8.94 (s, 2H). LC-MS: 4.74, 4.89 min. (M+H)=546.46.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8](OC)=[O:9])[CH2:4][O:3]1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1
Reactant: COC(=O)C[C@H]1COC(C)(C)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To an ice cooled solution of methyl (4S)-2,2-dimethyl-1,3-dioxolane-4-acetate (1.0 g, 5.74 mmol) in methanol (10 ml) was added portionwise NaBH4 (1.3 g, 34.4 mmol). After the addition was completed, the reaction mixture was stirred at room temperature for 3 hours. Water (40 ml) was added, and the resulting mixture was stirred for several minutes and concentrated in vacuo. The residue was extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo to give 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (808.9 mg, 96.4%) as a colorless oil.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[I:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>CCO>[CH2:2]([O:4][C:5](=[O:13])[C:6]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([I:14])=[CH:16][CH:17]=1)([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3]
Reactant: BrCc1ccc(I)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(I)cc1)C(=O)OCC

Procedure:
220 mg (10 mmol) sodium in small pieces are added to 15 mL EtOH. After 15 min 1.65 mL (9.70 mmol) 2-methyl-malonic acid diethyl ester are added. The mixture is stirred at reflux for 15 min and subsequently 3.00 g (10.1 mmol) 4-iodobenzyl bromide are added. The mixture is stirred at reflux for 12 h. After that time, the solvent is evaporated and the residue is purified by column chromatography (silicia gel; cyclohexane:EtOAc 98:2) to yield the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.O.C([O:16][C:17](=O)[CH2:18][CH3:19])C>>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][C:17](=[O:16])[CH2:18][CH3:19])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC
Reactant: CC(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a suspension of NaH (60%, 106 mg, 4.44 mmol) in 2 mL propionic acid ethyl ester was added 1-(4-methylphenyl)ethanone (500 mg, 3.7 mmol) at 0-5° C. The reaction mixture was stirred overnight at rt. Water was added, and the mixture was extracted with EtOAc (3×50 mL). The organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=10/1) to give the title compound (370 mg, 52%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.22 (3H, m), 2.45 (5H, m), 6.17 (2H, s), 7.27 (2H, d, J=10 Hz), 7.81 (2H, d, J=11.2 Hz). [M+H] Calc'd for C12H14O2, 191; Found, 191.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](B(O)O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[O:1]1[CH2:2][CH2:3][O:4][C:5]2[CH:10]=[C:9]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[N:21][C:22]=4[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc2c(c1)OCCO2
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc3c(c2)OCCO3)c2c(N)ncnc21
Temperature: 80 °C
Yield: 15 %

Procedure:
A solution of 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (26 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA54 (6 mg, 15% yield). ESI-MS (M+H)+ m/z calcd 312.1, found 312.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[CH3:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[C:14]([CH3:27])[C:12]=1[NH2:13]>>[NH2:13][C:12]1[C:14]([CH3:27])=[CH:15][C:16]([C:2]2[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=2)=[CH:17][C:11]=1[CH3:10]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Reactant: Cn1ncc(Cl)cc1=O
Product: Cc1cc(-c2cnn(C)c(=O)c2)cc(C)c1N
Temperature: 60 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 5-chloro-2-methylpyridazin-3(2H)-one and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 60° C. LC (method 9): tR=0.79 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@H:13]([C:29](=[O:31])[NH2:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH:22]=2)=[CH:17][CH:16]=1)=[O:11].[CH2:39]([O:41][P:42]([C:47]([F:59])([F:58])[C:48]1[CH:53]=[CH:52][C:51]([CH2:54][C:55](O)=[O:56])=[CH:50][CH:49]=1)([O:44][CH2:45][CH3:46])=[O:43])[CH3:40]>>[CH2:39]([O:41][P:42]([C:47]([C:48]1[CH:49]=[CH:50][C:51]([CH2:54][C:55](=[O:56])[NH:8][C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:29](=[O:31])[NH2:30])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH:22]=3)=[CH:19][CH:20]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:52][CH:53]=1)([F:59])[F:58])(=[O:43])[O:44][CH2:45][CH3:46])[CH3:40]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(CC(=O)O)cc1
Reactant: NC(=O)[C@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)NC(=O)[C@@H](N)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(C3=CC(=O)NS3(=O)=O)cc2)C(N)=O)cc1

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 10, using 1.38-B of Step 2 and {4-[(diethoxy-phosphoryl)-difluoro-methyl]-phenyl}-acetic acid (Biochemistry, 2003, 42, 12792) as the starting materials. LCMS found for C34H38F2N4O9PS (M+H)+: m/z=747.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[OH:33])=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH3:14]>N1C=CC=CC=1.Cl>[CH2:13]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[O:33][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH3:14]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12CC
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Add decanoyl chloride (1.9 g.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one (1.3 g.) in pyridine (12.5 cc.) and allow the mixture to stand at room temperature overnight. Pour the mixture in 2N hydrochloric acid and extract with ether. Wash, dry and evaporate the extracts and recrystallize the residue from benzene-hexane to give the title compound (1.0 g.), m.p. 97°-97.5°; ultraviolet absorption peak at 239 mμ (ε16,500); infrared absorption peaks at 5.74; 5.99, 6.17 μ.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:24][C:25](=[O:36])[C@H:26]([NH:28]C(OC(C)(C)C)=O)[CH3:27]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:24][C:25](=[O:36])[C@H:26]([NH2:28])[CH3:27]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
TFA (0.5 ml) was added drop wise to a solution of (R)-N-[2-chloro-4-(phenylsulphonyl)phenyl]-2-(t-butoxycarbonylamino)propanamide (Method 2) (0.090 g) in dry DCM (5 ml). The resulting mixture was stirred at room temperature for 3 hours. Volatile material was removed by evaporation. The resulting residue was re-dissolved in DCM (10 ml), and volatile material was removed by evaporation. This was repeated, the resulting residue was dried for 30 minutes on a high vacuum line. The residue was then dissolved in DCM and passed through a Varian Isolute SPE column containing basic residues, with DCM as the eluent to give the title compound (0.067 g) as a gum. NMR (CDCl3): 1.32-1.40 (d, 3H), 1.52 (brs, 2H), 3.51-3.64 (q, 1H), 7.40-7.55 (m, 3H), 7.71-7.8(m, 1H), 7.81-7.95 (m, 3H), 8.58-8.65 (m, 1H), 10.46 (brs, 1H). MS: (ESP−) 339.3 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:14]([Cl:46])=[C:15]([NH:21][C:22]3[N:27]=[C:26]([N:28]([CH:38]4[CH2:40][CH2:39]4)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:25]4=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]4[N:23]=3)[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=2)[CH2:9][C@H:8]1[O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49].C(N(CC)CC)C>ClCCl>[Si:48]([O:47][C@H:8]1[C@H:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([NH:21][C:22]3[N:27]=[C:26]([N:28]([CH:38]4[CH2:40][CH2:39]4)[CH2:29][C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)[C:25]4=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]4[N:23]=3)[C:14]=2[Cl:46])[CH2:9]1)([C:51]([CH3:53])([CH3:54])[CH3:52])([CH3:49])[CH3:50]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)CCl)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
2-chloroacetyl chloride (7.56 mg, 0.067 mmol) in dichloromethane (0.5 mL) was added to a mixture of (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171D), (39 mg, 0.056 mmol) and triethylamine (0.016 mL, 0.112 mmol) in dichloromethane (1 mL) at 0° C. and the reaction mixture was stirred at for 1 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 5-40% ethyl acetate/dichloromethane to afford (+/−)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)-2-chloroacetamide (43 mg) as a white solid.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][C:30]1[N:35]=[N:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:36]=2)[N:35]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Cc1ccc(N)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (1.00 g, ˜80% purity, 1.87 mmol, 1.0 eq), 6-methylpyridazin-3-amine (CAS-Nr. 18591-82-7, 0.245 g, 2.24 mmol, 1.2 eq), N,N-diisopropylethylamine (0.33 mL, 1.87 mmol, 1.0 eq) and activated 3 Å molecular sieves in isopropanol (5.7 mL) was heated for 7 hours under reflux. On cooling, the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. UPLC analysis of the crude product indicated a purity of >90%. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:10])[CH3:9]
Reactant: CC(O)c1cccc(Cl)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cccc(Cl)n1
Yield: 87.5 %

Procedure:
A mixture of 1-(6-chloro-2-pyridyl)ethanol (2.13 g) and manganese dioxide (8.4 g) in chloroform (21 ml) was refluxed for 8 hours. After cooling, the mixture was filtered through celite pad and the filtrate was evaporated in vacuo. The residue was purified by distillation under reduced pressure to give 2-acetyl-6-chloropyridine (1.84 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4]([C:20]([O:22]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:3]1.[NH3:34]>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4]([C:20]([NH2:34])=[O:22])=[CH:3]1
Reactant: N
Reactant: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc3ccccc3c2)cc1=O
Solvent: C1CCOC1
Product: Cn1cc(C(N)=O)c(Nc2ccc3ccccc3c2)cc1=O
Yield: 87 %

Procedure:
2,3,4,5,6-Pentafluorophenyl 1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate in THF was reacted with conc. NH3 solution as for example 37, step B. The crude product was recrystallised (MeOH/EtOAc) to give 1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (87%); m.p. (MeOH/EtOAc) 254-257° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.56 (s, 1H), 8.35 (s, 1H), 7.95-7.86 (m, 4H), 7.74 (d, J=1.9 Hz, 1H), 7.53-7.42 (m, 3H), 7.39 (dd, J=8.7, 2.1 Hz, 1H), 5.86 (s, 1H), 3.37 (s, 3H). LCMS (ACPI−) 292 (100%). Anal. Calcd for C17H15N3O2: C, 69.6; H, 5.2; N, 14.3. Found C, 69.4; H, 5.2; N, 14.5.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH:14]=[CH:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22].[CH2:23](NC1C=CC=CC=1C)C=C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH:14]=[CH:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[C:10]1=[O:22]
Reactant: N[C@H]1CC=CCN(c2ccccc2)C1=O
Reactant: C=CCNc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1N1CC=CC[C@H](N)C1=O

Procedure:
(S,Z)-3-Amino-1-o-tolyl-3,4-dihydro-1H-azepin-2(7H)-one trifluoroacetate (17 mg, 0.051 mmol) was synthesized as described for the preparation of Intermediate 52 using N-allyl-2-methylaniline in step A. Anal. Calcd. for C13H16N2O m/z 216.2. found: 217.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:4]([CH3:22])[CH:3]=1.[C:23]1(B(O)O)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>C(OCC)(=O)C>[C:23]1([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[O:10])=[C:4]([CH3:22])[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Cc1cc(Br)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(C2=CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 150 °C
Yield: 69.7 %

Procedure:
To N-(4-bromo-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (50 mg, 0.14 mmol), cyclohexen-1-ylboronic acid (35 mg, 0.28), and Pd(dppf)C12-DCM (11 mg, 0.01 mmol) was added Na2CO3 (980 μL of 2 M, 1.96 mmol) and acetonitrile (2 mL). The reaction mixture was heated under microwave irradiation for 10 min at 150° C. under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel column chromatography (30-100% ethyl acetate/hexane) to obtain N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white solid (35 mg, 70%). N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (35 mg, 0.10 mmol) was stirred vigorously with 10% Pd/C (wet) (30 mg, 0.01 mmol) under an atmosphere of H2 for 30 min at 50° C. The reaction mixture was filtered, concentrated in vacuo, and purified by HPLC (30-95% CH3CN/5 mM HCl) to yield N-(4-cyclohexyl-2-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (20 mg, 57% yield). LC/MS m/z 361.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.94 (d, J=6.0 Hz, 1H), 12.24 (s, 1H), 8.89 (d, J=6.5 Hz, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.45 (m, 1H), 2.38 (s, 3H), 1.80-1.69 (m, 5H), 1.42-1.21 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([O:20][C:16](=[O:19])/[CH:17]=[CH:18]/[C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1(c2cccc(Br)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cccc(C2(C(=O)OCC)CC2)c1
Yield: 55.2 %

Procedure:
Ethyl 1-(3-bromophenyl)cyclopropanecarboxylate (740 mg, 2.75 mmol) was dissolved in acetonitrile (20 mL) and the solution was treated with ethyl acrylate (3.90 mL, 35.7 mmol) and tri-o-tolyl phosphine (83.7 mg, 0.275 mmol). The reaction mixture was stirred at room temperature until all of the tri-o-tolyl phosphine had dissolved. Palladium acetate (30.9 mg, 0.137 mmol) was added in a single portion and the reaction mixture was stirred at reflux for 16 hr. Palladium acetate was added (10 mg) and the reaction mixture was stirred for another 4 h. The solvent was removed under reduced pressure and the crude material was purified via flash chromatography (pentane/ethyl acetate 95/5 to 92/8) to afford (E)-ethyl 1-(3-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)cyclopropanecarboxylate (438 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 1.09-1.19 (m, 5H), 1.31 (t, 3H), 1.56-1.63 (m, 2H), 4.03-4.11 (m, 2H), 4.23 (q, 2H), 6.40 (d, 1H), 7.20-7.36 (m, 2H), 7.36-7.42 (m, 1H), 7.44-7.51 (m, 1H), 7.66 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][C:14]1[NH:13][CH:17]=[CH:16][N:15]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorophenacyl chloride (1.42 g, 6.4 mmol) and imidazole (1.18 g, 16 mmol) were heated in toluene (40 ml) at 75° C. for 2.25 hours. The mixture was concentrated to dryness in vacuo. The residue was dissolved in dichloromethane and washed with 5% aqueous potassium carbonate solution and water, dried and concentrated in vacuo. The crude product was purified by passage over a pad of silica gel, eluting with 5% methanol in dichloromethane to give 1-(2,4-dichlorophenyl)-2-imidazolylethan-1-one as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 4-chlorobenzylsulfide. The title compound was obtained in 74% yield following oxidation. 1HNMR (CDCl3) δ 2.46 (3H, s), 4.64 (2H, s), 6.75 (1H, d, JH,H=12.21), 7.18-7.57 (9H aromatic+1H ethylenic).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24](O)(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:24](=[O:33])[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1
Yield: 29 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (3.1 mL), cinnamic acid (1.7 g), WSC.HCl (2.1 g), and methylene chloride (100 mL), to give the captioned compound (1.0 g, 29%) as an oily product.