Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[CH3:10][C:11]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl.FC(F)(F)C1C=CC=C[C:29]=1[O:30]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:29]([N:17]2[CH2:18][CH2:19][CH:14]([O:13][C:12]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:11]=3[CH3:10])[CH2:15][CH2:16]2)=[O:30])=[CH:7][CH:6]=[N:5]1
Reactant: Cn1nccc(N)c1=O
Reactant: Cc1ccc(C)c(OC2CCNCC2)c1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: Cl
Product: Cc1ccc(C)c(OC2CCN(C(=O)Nc3ccnn(C)c3=O)CC2)c1
Yield: 43 %

Procedure:
Compound 55 is prepared from intermediate 4c and from 4-(2,5-dimethyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 43%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-])=O)[C:9]1=[O:21])[CH3:7])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[NH2:18])[C:9]1=[O:21])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a suspension of (R)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (5.34 g, 0.0184 mol) in ethanol (100 mL, 2 mol) was added ammonium chloride (9.840 g, 0.1840 mol) in water (100 mL, 6 mol). The reaction heated at 85° C. and iron (4.11 g, 0.0736 mol) was added in four portions 3 minutes apart. The reaction started turning dark and became completely brown. After 2 hours, the flask was removed from the oil bath and 150 ml of ethyl acetate was added in the flask. The organic layer was decanted and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a bright yellow oil.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][N:6]2[N:5]=1.[CH3:33][N:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[N:36]=[CH:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CCOC(C)=O.O.CN(C=O)C>[CH3:33][N:34]1[CH:38]=[C:37]([C:39]([NH:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][N:6]3[N:5]=[C:4]([CH3:3])[C:16]([C:17]4[S:18][C:19]([C:28]5[N:32]=[CH:31][NH:30][N:29]=5)=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)=[C:7]3[CH:8]=2)=[O:40])[N:36]=[CH:35]1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: Cc1nn2ccc(OCCN)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn2ccc(OCCNC(=O)c3cn(C)cn3)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 29.5 %

Procedure:
A mixture of 2-({2-methyl-3-[4-phenyl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridin-5-yl}oxy)ethanamine di-hydrochloride (100 mg, 0.20 mmol) obtained in Example 73-B(i), TEA (1.5 mL), 1-methyl-1H-imidazole-4-carboxylic acid (120 mg, 0.95 mmol), HOBT (220 mg, 1.6 mmol), EDCI (350 mg, 1.8 mmol) and DMF (10 mL) was stirred at rt for 14 h. To the reaction mixture were added water (200 mL) and EtOAc (200 mL) and the mixture was stirred for 30 min. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc and diisopropyl ether, and dried to give the title compound (31 mg, 29%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)=[N:10][C:9]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(OC)c(F)c3)cc(C(=O)OC)c2N)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC)c(F)c3)cc(C(=O)OC)c2N=[N+]=[N-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Methyl 3-amino-6-(3-fluoro-4-methoxyphenyl)-2-(4-(methoxycarbonyl)phenyl)-isonicotinate (1.00 g, 2.44 mmol) was dissolved in trifluoroacetic acid (12 mL) and the yellow solution was cooled in an ice bath. Powdered sodium nitrite (0.336 gm, 4.87 mmol) was added with stirring to give a dark red mixture. After 30 min, powdered sodium azide (1.59 g, 24.4 mmol) was added followed by diethyl ether (12 mL). The light red mixture was stirred in the ice bath for 30 min. The reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was washed with brine, dried with sodium sulfate, and the solvent removed. Flash silica gel chromatography (elution with a 1:1 mixture of methylene chloride and EtOAc) afforded methyl 3-azido-6-(3-fluoro-4-methoxyphenyl)-2-(4-(methoxycarbonyl)phenyl)isonicotinate (1.06 gm). 1H NMR (CDCl3) δ ppm 8.17 (2H, d, J=7.93 Hz), 8.01 (1H, s), 7.91 (2H, d, J=7.93 Hz), 7.82-7.88 (1H, m), 7.79 (1H, d, J=8.55 Hz), 7.04 (1H, t, J=8.55 Hz), 4.05 (3H, s), 3.96 (3H, s), 3.94 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]([F:17])([F:16])[F:15])[O:12][N:11]=[C:10]2[C:18]2[CH:19]=[CH:20][C:21](SC)=[C:22]([CH:25]=2)[C:23]#[N:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:29]1C=C(C=CC=1)C(OO)=O.[S:39](=[O:42])(O)[O-:40].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]([F:16])([F:15])[F:17])[O:12][N:11]=[C:10]2[C:18]2[CH:19]=[CH:20][C:21]([S:39]([CH3:29])(=[O:42])=[O:40])=[C:22]([CH:25]=2)[C:23]#[N:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CSc1ccc(C2=NOC(C(F)(F)F)C2c2cc(Cl)cc(Cl)c2)cc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C2=NOC(C(F)(F)F)C2c2cc(Cl)cc(Cl)c2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-(methylthio)benzonitrile (i.e. the product of Example 5) (0.42 g, 1.0 mmol) in 20 mL of dichloromethane was added 3-chloroperoxybenzoic acid (0.90 g of ˜77% peracid, 4.0 mmol) in one portion, and the mixture was stirred at ambient temperature overnight. Aqueous sodium bisulfite solution was added, and after several minutes solid potassium carbonate was added. The layers were separated, and the organic phase was dried over magnesium sulfate and concentrated to leave a solid. The solid was triturated with a mixture of diethyl ether and hexanes, collected on a glass frit, and dried in air to afford the title product, a compound of the present invention, as a white solid (0.38 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([OH:3])=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=C(C)C=C(C)C=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[C:11](=[O:13])[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]2=[O:3])=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1Cc2ccccc2C(=O)N1c1ccc(Cl)cc1

Procedure:
2-(2-Carboxyphenyl)acetic acid (9 g) and 4-chloroaniline (6.3 g) in mesitylene (200 ml) were heated at reflux for 18 h, under Dean and Stark conditions. On cooling, the crude product crystallised out and was filtered off. Recrystallisation from ethanol/ethyl acetate gave 2-(4-chlorophenyl)isoquinoline-1,3(2H,4H )-dione, m.p. 178°-80° C. A mixture of this product (2.8 g) and phosphoryl chloride (10 ml) was heated at reflux for 21 h, and excess phosphoryl chloride was then eveporated at reduced pressure. The residue was stirred in ice-water for 4 h. and the precipitate filtered off and suspended in 2% aqueous sodium bicarbonate for 5 minutes. It was again filtered off, taken up in dichloromethane (150 ml) dried and evaporated. Column chromatography of the residue gave a brown solid, which was recrystallised from isooctane/ethyl acetate, to give 3-chloro-2-(4-chlorophenyl)isoquinolin-1(2H)-one m.p. 125°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[C:13](F)[N:12]=2)[CH:9]=1)[C:5]#[N:6].[NH2:20][CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:24][N:23]=1>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[C:13]([NH:20][CH2:21][C:22]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)[N:12]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: NCc1n[nH]c2ncccc12
Reactant: N#Cc1cc(Cl)cc(Oc2nc(F)c(Cl)cc2F)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)cc(Oc2nc(NCc3n[nH]c4ncccc34)c(Cl)cc2F)c1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A solution of 50 mg (0.166 mmol) of 1-6 and 25 mg (0.166 mmol) of 1-3 in 1.5 mL of dry NMP was heated with stirring at 90° C. under nitrogen. After 7 hours, the reaction was stopped and cooled. The reaction mixture was diluted with water, and extracted twice with EtOAc. The combined EtOAc extracts were washed with water and brine, dried, filtered, and concentrated in vacuo to give a crude oil. The crude product was purified by reversed phase preparative HPLC on a Gilson apparatus to give the title product as a white amorphous solid. MS M+1=430. 1H NMR (CDCl3): 4.77 (d, 2H), 5.60 (br m, 1H), 7.17 (q, 1H), 7.34 (m, 1H), 7.36 (m, 1H), 7.39 (m, 1H), 7.50 (d, 1H), 8.01 (dd, 1H), 8.53 (m, 1H), 10.5-11.5 (br, 1H).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38]Br)=[CH:33][C:32]=1[NH:48][CH:49]=[O:50])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.O>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:38][C@@H:37]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:32]([NH:48][CH:49]=[O:50])[CH:33]=4)[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reactant: NCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 130 °C

Procedure:
To a solution of Intermediate 22 (0.4 g, 1.34 mmol) and (R)—N-(2-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)phenyl)formamide (0.62 g, 0.82 mmol) in dimethyl sulfoxide (3 mL) was added sodium iodide (0.59 g, 3.99 mmol) and sodium hydrogen carbonate (0.67 g, 8.03 mmol). The reaction mixture was heated under argon at 130° C. for 1 hour. The mixture was poured into water and extracted with ether. The organic layer was washed with water and brine and the solvent was removed under reduced pressure. The title compound was obtained as yellow foam (0.84 g, 73%) and used in the next step without further purification. MS (M+): 684.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([N:33]2[C:37](=[O:38])[CH2:36][CH2:35][C@@H:34]2[CH2:39][OH:40])[CH:3]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50].O>C(Cl)Cl>[CH3:48][S:49]([O:40][CH2:39][C@H:34]1[CH2:35][CH2:36][C:37](=[O:38])[N:33]1[C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])(=[O:51])=[O:50]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO)c(OCc1ccccc1)c2=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1COS(C)(=O)=O)c(OCc1ccccc1)c2=O
Temperature: 23 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a stirred solution of intermediate 192, (R)—N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.160 g, 0.291 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (81 μL, 0.582 mmol) and methanesulfonyl chloride (27 μL, 0.349 mmol). The reaction mixture was stirred at 23° C. for 4 h. Water (50 mL) was then added and the organic material was extracted with CH2Cl2 (2×50mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.178 g, 98% yield). The crude material was used without further purification for the next step: LCMS (M+H)+ m/z 629.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[C:29]([C:32]1[CH:33]=[C:34]([CH:38]=O)[N:35]([CH3:37])[CH:36]=1)(=[O:31])[CH3:30]>>[C:29]([C:32]1[CH:33]=[C:34]([C:38]2[N:12]([CH2:27][C:20]3[C:19]4[C:24](=[CH:25][CH:26]=[C:17]([Cl:16])[CH:18]=4)[N:23]=[CH:22][CH:21]=3)[N:11]=[C:10]3[C:9]=2[C:8](=[O:13])[N:7]([CH3:14])[C:6](=[O:15])[N:5]3[CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:35]([CH3:37])[CH:36]=1)(=[O:31])[CH3:30]
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: CC(=O)c1cc(C=O)n(C)c1
Product: CC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by 4-acetyl-1-methyl-1H-pyrrole-2-carbaldehyde. Mass: 517.14 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:12])([CH3:11])[CH2:4][CH2:5][CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:23])=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1>>[CH3:11][C:3]([CH3:12])([CH2:4][CH2:5][CH2:6][S:7](=[O:8])(=[O:9])[NH2:10])[CH2:2][O:1][C:14]1[C:15]([CH3:23])=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(C)(CO)CCCS(N)(=O)=O
Reactant: Cc1cc2ncnn2nc1Cl
Product: Cc1cc2ncnn2nc1OCC(C)(C)CCCS(N)(=O)=O

Procedure:
Using 5-hydroxy-4,4-dimethyl-1-pentanesulfonamide and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction was conducted as in Example 5 to produce the title compound. m.p. 171°-172° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.O1CCCC1.C[Si](C)(C)[C:35](F)([F:37])[F:36].[I-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23]4([C:35]([F:37])([F:36])[CH2:26]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=C1CCC(C)(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2(F)F
Temperature: 115 °C
Yield: 79 %

Procedure:
To a 10 mL microwave tube charged with tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methyl-4-methylenecyclohexyl)methoxy)benzoate (0.475 g, 1.27 mmol) and tetrahydrofuran (4 mL) was added trimethyl(trifluoromethyl)silane (0.375 mL, 2.54 mmol) and sodium iodide (0.42 g, 2.79 mmol). The reaction mixture was heated at 115° C. for 1 hour. After cooling to ambient temperature, additional trimethyl(trifluoromethyl)silane (0.375 mL, 2.54 mmol) and sodium iodide (0.42 mg, 2.79 mmol) were added. The reaction was heated at 115° C. for another 1 hour. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 5% ethyl acetate in hexanes) afforded the title compound (0.426 g, 79%) as a colorless oil: MS (ES+) m/z 369.1 (M−55).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([O:14]C)=[O:13])=[CH:5][C:4]=2[N:3]1[CH2:16][CH:17]=[CH2:18].[OH-].[Na+].Cl>O1CCOCC1.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5][C:4]=2[N:3]1[CH2:16][CH:17]=[CH2:18]
Reactant: C=CCn1c(=O)ccc2ncc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1c(=O)ccc2ncc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of methyl 6-oxo-5-(2-propen-1-yl)-5,6-dihydro-1,5-naphthyridine-3-carboxylate (0.809 g, 3.32 mmol) in 1,4-dioxane (10 ml) and water (5 ml) was added 2M NaOH (2 ml) and the reaction was stirred at rt for 2 h. The pH of the mixture was then adjusted to 2-3 with 2M HCl and extracted three times with EtOAc. The combined organic phases were then dried and evaporated to give the desired product as a solid (0.689 g, 90%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:9]([O:11][C:12](=[O:15])CN)[CH3:10].C([N:18](CC)CC)C>CCO>[CH2:9]([O:11][C:12]([NH:18][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:15])[CH3:10]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CN
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCNC(=O)OCC

Procedure:
Ethyl acrylate (a) (50 mL, 460 mmol, 1.1 eq), glycine ethyl ester hydrochloride (b) (58.4 g, 418 mmol, 1 eq), and triethylamine (58.3 mL, 418 mmol, 1 eq) in absolute EtOH (960 mL) was stirred at ambient temperature for approximately 72 h. After reaction was complete, volatile components were removed under vacuum and the crude intermediate (c) was carried on directly.
Reaction SMILES: [SH:1][CH:2]([SH:17])[C:3]([SH:16])([SH:15])[C:4]([O:6][CH2:7][C:8]([CH2:13][OH:14])([CH2:11][OH:12])[CH2:9][OH:10])=[O:5].[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C(N(CC)CC)C.C(#N)C>[C:21]([O:14][CH2:13][C:8]([CH2:11][OH:12])([CH2:9][O:10][C:21](=[O:22])[CH2:20][C:19]([CH3:18])=[O:23])[CH2:7][O:6][C:4](=[O:5])[C:3]([SH:15])([SH:16])[CH:2]([SH:1])[SH:17])(=[O:22])[CH2:20][C:19]([CH3:18])=[O:23]
Reactant: C=C1CC(=O)O1
Reactant: O=C(OCC(CO)(CO)CO)C(S)(S)C(S)S
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)CC(=O)OCC(CO)(COC(=O)CC(C)=O)COC(=O)C(S)(S)C(S)S
Temperature: 70 °C

Procedure:
To a solution of 20.0 g. ((0.041 mol) of pentaerythritol tetramercaptopropionate in 20 g. of acetonitrile was added 7.9 g. (0.094 mol. 2.3 equiv.) of diketene. Upon addition of triethylamine catalyst (30 mg) an exotherm of 17° C. was observed. After 30 minutes the reaction mixture was warmed to 70° C. for an additional 30 minutes to ensure complete reaction. Solvent was removed on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:20]([C:23]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[NH:25][N:24]=1)([CH3:22])[CH3:21].[H-].[Na+]>C(N(CC)CC)C>[ClH:1].[CH:13]1([NH:19][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:24]3[C:23]([CH:20]([CH3:21])[CH3:22])=[CH:27][C:26]([CH:28]([CH3:30])[CH3:29])=[N:25]3)[N:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: CC(C)c1cc(C(C)C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)n(-c2nc(NC3CCCCC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cyclohexylamine and 3,5-diisopropylpyrazole with sodium hydride as base instead of triethylamine. Mp. 83.4-85.3° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[H-].[Na+].Br[CH2:16][C@@:17]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:19][CH:18]1[CH2:20]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:7]1([S:4]([C:3]2([S:2][CH3:1])[CH2:20][C@H:18]3[C@:17]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)([CH2:19]3)[CH2:16]2)(=[O:5])=[O:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSCS(=O)(=O)c1ccccc1
Reactant: Clc1ccc([C@]2(CBr)CC2CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 40 °C
Yield: 33.1 %

Procedure:
1-((Methylthio)methylsulfonyl)benzene (2.95 g, 14.6 mmole) was dissolved in dry dimethylforamide (DMF, 40 mL). Sodium hydride (1.75 g, 36.5 mmol) was added portion wise under nitrogen atmosphere at 0° C. The mass was gradually heated to 40° C. and maintained for 30 min at 40° C. A solution of (1S)-1,2-bis(bromomethyl)-1-(3,4-Dichlorophenyl)cyclopropane (5.65 g, 14.65 mmol) in DMF (10 mL) was added dropwise for 30 minutes at 0° C. The temperature of the reaction mass was brought to room temperature slowly and maintained for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (10:90)). The reaction mass was quenched with water. The aqueous layer was extracted with diethyl ether (2×250 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 8 g of crude oil that was purified by column chromatography (silica gel, ethyl acetate/hexane (4:96) to yield 2 g (33%) of product. 1H NMR δ(300 MHz,CDCl3): 1.73 (1H,m), 1.85 (2H,m), 2.04 (3H,s), 2.29 (2H,m), 2.54 (1H,m),2.88 (1H, dd, J=15 Hz), 7.12 (1H,d,J=3 Hz), 7.15 (1H,d,J=3 Hz), 7.25 (1H,m), 7.3 (1H,d,J=9 Hz), 7.55-7.57 (2H,m), 7.91 (2H,m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[C:28]([CH3:41])=[C:29]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:30](N)=[CH:31][CH:32]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:29]2[C:28]([CH3:41])=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(F)ccc(N)c1Nc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccn3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.52 g, 8.1 mmol) in DCM (15 mL) was added triethyloxonium tetrafluoroborate (1.63 g, 8.6 mmol) and the reaction mixture stirred at RT for 2 h, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (15 mL). 4-fluoro-3-methyl-N2-pyridin-2-yl-benzene-1,2-diamine (1.0 g, 5.1 mmol) was added and the reaction heated at 75° C. for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (1.29 g, 76%). LCMS (Method C): RT=3.22 min, [M+H]+=371.