Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH3:15])([CH3:16])[CH:12]([CH3:13])[CH3:14])[NH:8]1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)C(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 57 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 78a (1.5 g, 6.2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.1 g, 3.5 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][C:10]3[C:15]([C:16]=2[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>>[C:1]1([C:7]2[C:8](=[S:33])[NH:9][C:10]3[C:15]([C:16]=2[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)OC(=O)c1c(-c2ccccc2)c(=O)[nH]c2ccccc12
Product: CC(C)OC(=O)c1c(-c2ccccc2)c(=S)[nH]c2ccccc12

Procedure:
307 mg (1 mmol) of isopropyl 3-phenylquinolin-2(1H)-one-4-carboxylate (Example 7) are reacted with Lawesson's reagent according to the process described in Example 5 and purified by chromatography on silica gel as indicated above (mobile phase: n-heptane/ethyl acetate=411).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[C:17]([F:18])=[C:16]([N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH3:20])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Na+].Cl>C1COCC1>[F:18][C:17]1[C:5]([C:4]([OH:25])=[O:3])=[CH:6][C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])=[CH:15][C:16]=1[N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH3:20]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)c(F)c(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)c(F)c(N(C)S(C)(=O)=O)c1
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Dissolve the 6-fluoro-5-(methanesulfonyl-methyl-amino)-N-methyl-N-propyl-isophthalamic acid ethyl ester (110 mg, 0.30 mmol) in THF (7.5 mL). Add 1 N sodium hydroxide solution (1.48 mL, 1.48 mmol) and stir the resulting biphasic mixture vigorously for 4 h. Acidify with 1 N HCl (1.55 mL, 1.55 mmol) and concentrate the solution to a volume of about 3 mL. Extract the solution with diethyl ether (2×20 μL). Combine the organic layers, dry (magnesium sulfate) and concentrate to give the title compound as a solid (95.2 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH2:22][OH:23].O[C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH2:22][O:23][C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1ccc(F)c(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)ccc3F)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
The crude (S)-(4-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 18d (150 mg, 0.45 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (94 mg, 0.45 mmol) and triphenylphosphine (177 mg, 0.68 mmol) were dissolved in 5 mL of dichloromethane. The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (136 mg, 0.68 mmol). The reaction solution was warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((4-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 18e (150 mg, yield 65.8%) as a colorless slime.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12]([O:14][CH2:15][CH2:16]Br)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OC(=O)C)C>[CH2:12]([O:14][CH2:15][CH2:16][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: CCOCCBr
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCON=C(C(C)=O)C(=O)OCC
Yield: 97.7 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer 40 g.), ethoxyethyl bromide (41.1 g.), potassium carbonate (54.1 g.), N,N-dimethylformamide (65 ml.) and ethylacetate (65 ml.) were treated in a similar manner to that of Example A-(1) to give ethyl 2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer, 56.8 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7](O)=[O:8].C(Cl)(=O)C([Cl:20])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([Cl:20])=[O:8]
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCC(=O)Cl
Reaction time: 0.75 h

Procedure:
A suspension of (2-methoxy-4-nitro-phenoxy)acetic acid [FEBS Lett. (1983), 153(2), 431], (3.12 g 15.9 mmol) in dichloromethane (100 ml) was cooled down to 0° C. in an ice bath before oxalyl chloride (5.26 g, 41.7 mmol) was added. The reaction mixture was stirred for 45 minutes, giving a clear solution. The solvents were removed in vacuo to give (2-methoxy-4-nitro-phenoxy)-acetyl chloride as a pale yellow solid. (3.41 g, 100%);
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]1[CH3:22])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:17]([CH3:22])[CH2:18]2)=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Clc1ccc(Cl)nn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc(Cl)nn2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
A mixture of 3,6-dichloropyridazine (298 mg, 2 mmol) and (R)-1-N-Boc-2-methyl piperazine (401 mg, 2.0 mmol) in N,N-diisopropylethylamine (0.7 mL, 4 mmol) was stirred at 120° C. for 5 h. The reaction mixture was diluted with ethyl acetate and washed with brine (2×), then dried over MgSO4. The salts were removed by filtration and the filtrate was concentrated and the residue was purified by chromatography on silica gel eluting with 20% to 80% ethyl acetate in hexane to give compound 11 as a light yellow solid (511 mg, 82%). 1H NMR (500 MHz, CD3OD) δ 7.24 (1H, d, J=10 Hz), 6.88 (1H, d, J=10 Hz), 4.38 (1H, br s), 4.17 (1H, d, J=10 Hz), 4.05-3.97 (2H, m), 3.39 (1H, dd, J=15 Hz, J=5 Hz), 3.29 (1H, ddd, J=15 Hz, J=10 Hz, J=5 Hz), 1.51 (9H, s), 1.21 (3H, d, J=10 Hz) ppm; LCMS-ESI (POS), M/Z, M+1: Found 313.1, Calculated 313.1.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][CH2:23]Cl.C(O)(=O)C>CN(C)C=O>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:21][O:22][CH3:23])[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COCN1C(=O)N([C@H](C)c2ccccc2)[C@H]2COC(=O)[C@H]21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
4.0 g (93 mmol) sodium hydride (55 percent in oil) was added in 10 portions in 2 hours at -10° C. under argon to a solution of 19 g (77 mmol) of (3as,6aR)[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]-imidazol-2,4-(3H,3aH)-dione and 9.42 g (120 mmol) of chloromethyl methyl ether in 200 ml of dried N,N-dimethylformamide. The reaction mixture was stirred at 5° C. for 2 hours and then at room temperature for another 2 hours. Then 2 ml of acetic acid was added. Then the mixture was evaporated to dryness. Then the residue was taken up in 50 ml of water and 100 ml of dichloromethane, the phases were separated and the aqueous phase was extracted 2 times with 100 ml of dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. After chromatographing the oily residue over silica gel with 500 ml of dichloromethane/ethyl acetate and concentration of the fractions 4.0 g (18 percent) of the title product was obtained as white powder. Concerning the product:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>ClCCl>[CH3:21][S:22]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(C)(=O)=O)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (2.53 g, 9.64 mmol) (Intermediate 10.1), methanesulfonyl chloride (1.12 ml, 14.47 mmol), and triethylamine (2.94 ml, 21.22 mmol) in dichloromethane (50 ml) is stirred for 30 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 3.24 g (99%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 7.16 min (tR(SM) 6.64 min). MS (ESI) m/z (C17H16N4O2S) 341.1 (M+1, 100) Finnegan LCQ.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][CH:27]([O:34][CH3:35])[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][CH3:33].[CH:36]([C:39]1[S:40][CH:41]=[C:42]([C:44]([N:46]2[CH2:51][C:50]3([CH2:56][CH2:55][N:54]([CH2:57][CH2:58][O:59][C:60]4[CH:73]=[CH:72][CH:71]=[CH:70][C:61]=4[CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67](O)=[O:68])[CH2:53][CH2:52]3)[O:49][CH2:48][CH2:47]2)=[O:45])[N:43]=1)([CH3:38])[CH3:37].CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:30]([N:29]([CH2:28][CH:27]([O:26][CH3:25])[O:34][CH3:35])[C:67](=[O:68])[CH2:66][CH2:65][O:64][CH2:63][CH2:62][C:61]1[CH:70]=[CH:71][CH:72]=[CH:73][C:60]=1[O:59][CH2:58][CH2:57][N:54]1[CH2:53][CH2:52][C:50]2([O:49][CH2:48][CH2:47][N:46]([C:44]([C:42]3[N:43]=[C:39]([CH:36]([CH3:38])[CH3:37])[S:40][CH:41]=3)=[O:45])[CH2:51]2)[CH2:56][CH2:55]1)[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)O)CC3)C2)cs1
Reactant: CCCCNCC(OC)OC
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: CCCCN(CC(OC)OC)C(=O)CCOCCc1ccccc1OCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Reaction time: 1 h

Procedure:
HATU (0.337 g) was added to a stirred solution of N-(2,2-dimethoxyethyl)butan-1-amine (0.105 g), 3-(2-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-acid (0.390 g) (example 178 step d) and Hunig's Base (0.516 mL) in N,N-dimethylformamide (3 mL). After 1 h, the solution was partitioned between ethyl acetate and brine. The ethyl acetate layer was washed with brine (×3) and evaporated in vacuo. Purification was silica gel chromatography eluting with 10% triethylamine in ethyl acetate. Yield 0.4 g.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH2:15][CH2:16][CH3:17])=[O:14])=[CH:27][CH:28]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCCc1oc(-c2ccccc2)nc1C(=O)O
Product: CCCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-propyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H26N4O3 (m/e) 394, obsd 395 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH:12]=1)#[N:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH:7]=[CH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH:12]=1)#[N:2]
Reactant: N#Cc1cc2c([nH]c1=O)CCc1ccccc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: N#Cc1cc2c(ccc3ccccc32)[nH]c1=O

Procedure:
Add 11.1 gm of 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one to 1500 ml of anhydrous 1,4-dioxane containing 33.0 gm of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). Heat the system at reflux for 16 hours. Filter the solution and isolate the title compound.
Reaction SMILES: [CH2:1]([Sn:11]([CH2:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])[CH3:28])(C1C=CC(F)=CC=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:36]Cl>C(Cl)(Cl)Cl>[CH2:1]([Sn:11]([Cl:36])([CH2:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])[CH3:28])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: ClCl
Reactant: CC(C)(C[Sn](CC(C)(C)c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)c1ccc(F)cc1)c1ccccc1
Yield: 101.3 %

Procedure:
Dineophyl-di(parafluorophenyl)tin (62.1 g, 0.108 mol) prepared above was dissolved in chloroform (200 g). While the resulting solution was maintained at -15° to -20° C., chlorine gas (7.6 g, 0.216 gram atom) was introduced. The mixture was then concentrated under reduced pressure to give 56 g of dineophyl-parafluorophenyltin chloride as a pale-yellow liquid. Gas chromatography analysis indicated 87.5% purity of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](F)[N:23]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:29][C:30]1[CH:31]=[C:32]([CH2:36][NH2:37])[CH:33]=[CH:34][CH:35]=1>CS(C)=O>[Cl:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:37][CH2:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)[N:23]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: NCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 40 h
Yield: 89.3 %

Procedure:
A mixture of tert-butyl 4-(5′-chloro-6-fluoro-2,4′-bipyridin-2′-yl-amino)piperidine-1-carboxylate (200 mg, 0.492 mmol), DMSO (2 ml), TEA (0.137 ml, 0.983 mmol) and (3-fluorophenyl)methanamine (554 mg, 4.42 mmol) reaction mixture was flushed with argon and stirred at 100° C. for 40 hr, as the reaction mixture progress was followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (3), saturated salt solution (1×), dried over sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 12 g column, eluting from 0%-35% ethyl acetate with hexane. The desired fractions were collected and concentrated to constant mass, giving 225 mg of the title compound as a free base. LCMS (m/z): 512.3 (MH+), retention time=0.91 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15](Cl)=[N:16][C:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22](Cl)[CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+]>CO>[CH2:19]([C:17]1[N:16]=[C:15]([O:29][CH3:28])[C:12]2[CH2:13][CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][C:11]=2[N:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[O-]
Reactant: Clc1cccc(Cc2nc(Cl)c3c(n2)CCN(Cc2ccccc2)CC3)c1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2

Procedure:
2,7-dibenzyl-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of Step B (86 mg, 0.23 mmol) was dissolved in methanol (10 ml) and sodium methoxide (25 mg, 0.47 mmol) was added. The reaction was refluxed under nitrogen for 16 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was separated, washed with brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo to afford a colourless oil, 75.5 mg, 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[SH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: Sc1ccncc1
Solvent: CCO
Product: Clc1cccc(CSc2ccncc2)c1
Yield: 55.2 %

Procedure:
3-Chlorobenzyl chloride (1.61 g) and 4-mercaptopyridine (1.11 g) in ethanol (10 ml) were heated at reflux for 4 hours and cooled. Crystals which precipitated were removed by filtration and dried to give the title compound as the hydrochloride (1.3 g) mp 222°-4° C. (Found: C, 52.6; H, 4.3; N, 5.1. C12H10ClNS requires C, 52.95; H, 4.1; N, 5.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccccc4Cl)cc3c2C1
Yield: 72.7 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 5.7 mg (0.051 mMol) 2-chlorobenzoyl chloride, 12.3 mg (73%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][S:13]([CH3:16])(=[O:15])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[SH:48][CH2:49][C:50]([OH:52])=[O:51]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([S:48][CH2:49][C:50]([OH:52])=[O:51])=[O:9])=[CH:5][C:4]=1[O:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: O=C(O)CS
Reactant: COc1ccc(C(=O)O)cc1OS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)SCC(=O)O)cc1OS(C)(=O)=O
Temperature: 50 °C
Yield: 32.3 %

Procedure:
To a solution of 4-methoxy-3-(methylsulfonyloxy)benzoic acid (prepared in an analogous manner to that described in Scheme 23, Step 2 and 3) (0.362 g, 1.470 mmol) in dry DMF (10.7 ml), HATU (0.559 g, 1.470 mmol) and N-methylmorpholine (0.162 ml, 1.470 mmol) were added. The resulting mixture was stirred at 50° C. under nitrogen until complete conversion of the starting acid into the activated specie (detected by UPLC-MS). Then the solution was allowed to warm to RT and 2-mercaptoacetic acid (0.102 ml, 1.470 mmol) was added drop wise; the resulting mixture was stirred overnight at RT. The solvent was removed under vacuum and the residue was partitioned between EtOAc and HCl 1N; the organic phase was dried over Na2SO4 and the solvent was removed. The crude was purified by preparative HPLC to afford 2-(4-methoxy-3-(methylsulfonyloxy)-benzoylthio)acetic acid (0.152 g, 0.474 mmol, 32.3% yield, MS/ESI+ 342.9 [MNa]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[N:9]([CH2:12][C:13](OCC)=[O:14])=[C:10]=[S:11]>C(#N)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][N:1]2[C:13](=[O:14])[CH2:12][NH:9][C:10]2=[S:11])[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=O)CN=C=S
Solvent: CC#N
Product: O=C1CNC(=S)N1CCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
Histamine (111 mg, 1 mmol) and ethyl isothiocyanatoacetate (145 mg, 1 mmol) were dissolved in acetonitrile (6 mL), and the mixture was stirred at room temperature (25° C.) for 10 minutes. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol (4/1 (volume ratio)) as an eluent, to give 3-(2-(1H-imidazol-4-yl)ethyl)-2-thioxoimidazolidin-4-one in a yield of 167 mg (yield 79.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]C(N(OC)C)=O)=[CH:6][CH:5]=[C:4]([CH3:15])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-:26].[Na+]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:26]
Reactant: CON(C)C(=O)Cc1ccc(C)nc1Cl
Reactant: [OH-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C=O)c(Cl)n1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of 2-chloro-N-methoxy-N,6-dimethylpyridine-3-carboxyamide (1.30 g, 5.83 mmol) in dichloromethane (15 mL) was added with diisobutylaluminum hydride (0.99 M solution in toluene, 12 mL, 11.66 mmol) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 2 M aqueous sodium hydroxide, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 2-chloro-6-methylnicotinaldehyde (828 mg, 91%) as pale yellow oil.