Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)C#N)=C(C3C=CC=CC=3)[NH:17][C:16](=[O:34])[NH:15]2)[CH:7]=[C:8]([N+]([O-])=O)[C:9]=1[OH:10])C.[CH2:35]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[C:45]=1[OH:46])[CH:41]=O)[CH3:36].NC(N)=O.Cl>C(O)C>[O:10]1[C:9]2[CH:8]=[CH:7][C:6]([C:14]3[NH:15][C:16](=[O:34])[NH:17][CH:41]([C:40]4[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[C:45]([OH:46])=[C:38]([O:37][CH2:35][CH3:36])[CH:39]=4)[C:19]=3[C:20]3[CH:27]=[CH:26][CH:25]=[CH:22][CH:21]=3)=[CH:5][C:4]=2[O:3][CH2:1]1
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(C#N)c2)cc([N+](=O)[O-])c1O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: NC(N)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc4c(c3)OCO4)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 130 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-2-phenylethanone (Intermediate 29) (400 mg, 1.7 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (352 mg, 1.7 mmol), and urea (230 mg, 5.0 mmol) in 10 mL of ethanol was added 0.2 mL of concentrated HCl solution, the mixture was stirred at 130° C. overnight. After the solvent was removed under reduced pressure, the residue was purified by preparative HPLC (35-65% acetonitrile+0.1% trifluoroacetic acid in water, over 15 min.) to give Compound 61 (92.5 mg, yield 11.7%). 1H NMR (CD3OD 400 MHz): δ 7.60 (s, 1H), 7.18 (s, 1H), 7.12-7.09 (m, 3H), 6.92 (d, J=7.2 Hz, 2H), 6.78 (d, J=8.0 Hz, 1H), 6.71 (m, 2H), 5.92 (s, 2H), 5.32 (s, 1H), 4.11-4.03 (m, 2H), 1.41 (t, J=7.2 Hz, 3H); MS (ESI): m/z 476.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>N1C=CC=CC=1>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cc2F)C1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Amino-2-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene (27.33 g, 0.093 M) was dissolved in dry pyridine (150 ml) and cooled under nitrogen with stirring to 0°. Ethyl chloroformate (11.01, 0.102 M) was added dropwise, and the mixture stirred 30 minutes at the same temperature. Ice-water (250 ml) was added, and stirring continued for 1 hour. The resulting precipitate was collected, washed thoroughly with water, and dried, to give the desired product of sufficient quality for use without purification (33.6 g). MS (ESP): 368 (MH+) for C18H26FN3O4.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21]([F:22])=[CH:20][C:19]3[C:23](=[O:29])[C:24]([C:26]([OH:28])=[O:27])=[CH:25][N:17]4[C:18]=3[C:13]=2[CH2:14][CH2:15][N:16]4[CH3:30])[CH2:7]1.[CH3:31]O>>[NH2:5][C@H:6]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21]([F:22])=[CH:20][C:19]3[C:23](=[O:29])[C:24]([C:26]([O:28][CH3:31])=[O:27])=[CH:25][N:17]4[C:18]=3[C:13]=2[CH2:14][CH2:15][N:16]4[CH3:30])[CH2:7]1
Reactant: CO
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1N
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn2c3c(c(N4C[C@@H](N)[C@@H](C)C4)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Yield: 72 %

Procedure:
2 ml of thionyl chloride was added to 20 ml of methanol while cooling on ice, and then this solution was stirred at room temperature. 358 mg of the compound (30) obtained in Example 5 was added to the solvent, and the solution was heated at reflux for 8 hours. The solvent was removed and 40 ml of chloroform and 20 ml of water were added to the residue. The solution was alkalized with sodium hydrogen carbonate, and the organic layer was dried over magnesium sulfate. The solvent was removed by distillation. To the residue, ether was added and then ethyl acetate was added to form crystals. They were filtered off and washed with ethyl acetate in this order to obtain 270 mg of a title compound (121) (yield: 72%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][C:20](=[N:31][OH:32])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1CCN(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCN(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.5 %

Procedure:
A mixture of 0.20 g of 1-[2-(4-chloro-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-piperidinone, 0.04 g of hydroxylamine hydrochloride, 0.09 g of sodium acetate and 4 ml of methanol was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was added with aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, and dried, and the solvent was evaporated to give 0.25 g of a colorless solid. Recrystallization from ethyl acetate gave colorless crystals having the melting point of from 201 to 207° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[O:7]C2.[O-][Mn](=O)(=O)=O.[K+].[C:21]([O-:24])([O-:23])=O.[Na+].[Na+]>O>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([C:8]([OH:14])=[O:7])[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:21]([OH:24])=[O:23]
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)O)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
5,6-Dimethoxyisobenzofuran-1(3H)-one (3.171 g, 16.33 mmol) was treated with a solution of KMnO4 (2.57 g, 16.26 mmol) and Na2CO3 (1.542 g, 14.55 mmol) in water (110 ml). The solution was stirred at room temperature for 24 hours, then insoluble material was removed by filtration. The filtrate was cooled with an ice-water bath and acidified with concentrated aqueous HCl. The acidic solution was extracted three times with ethyl acetate (500 ml). The combined organic layers were dried over sodium sulfate and evaporated to dryness to give 600 mg of desired compound. The aqueous phase was then concentrated to 20 ml and a white solid precipitated. After filtration 500 mg desired compound were recovered. The two portions were collected to afford 4,5-dimethoxyphthalic acid as a white powder (1.1 g, 4.87 mmol, 30% yield). MS/ESI+ not detectable [MH]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=O)[C:18](O)=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:18](=[O:19])[C:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[N:11]2)([O-:3])=[O:2]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-Nitro-benzene-1,2-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-Nitro-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:56]2[N:57]=[C:58]([NH:61][C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[S:59][CH:60]=2)\[C:25]([NH:27][CH:28]2[C:54](=[O:55])[N:30]3[C:31]([C:38]([O:40][CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])=[C:32]([CH2:36]Cl)[CH2:33][S:34](=[O:35])[C@H:29]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:81].[Na+].C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:56]2[N:57]=[C:58]([NH:61][C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[S:59][CH:60]=2)\[C:25]([NH:27][CH:28]2[C:54](=[O:55])[N:30]3[C:31]([C:38]([O:40][CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])=[C:32]([CH2:36][I:81])[CH2:33][S:34](=[O:35])[C@H:29]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CI)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The residue obtained in (B) was dissolved in 40 ml of acetone, and 990 mg (6.6 mmol) of sodium iodide was added. The mixture was stirred at room temperature for 30 minutes. Then, 120 ml of ethyl acetate and 20 ml of a 5% sodium thiosulfate aqueous solution were added to the reaction solution for liquid separation. The organic layer was washed with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The concentrated residue was subjected to silica gel flush column chromatography (ethyl acetate/n-hexane=1/2). The fraction containing the desired product was collected, and concentrated under reduced pressure, and isopropyl ether was added to the residue to obtain 2.92 g of a powder of the above identified compound (yield from A: 80.3%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Br:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22].C[O-].[Na+]>CO>[Br:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:20][C@@H:21]([CH3:22])[C:23]([OH:25])=[O:24])=[O:7])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)c1nc(Br)c2ccccc2c1O)C(=O)O
Temperature: 160 °C

Procedure:
400 mg of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 890 mg of (L)-Alanine was suspended in a 20 ml solution of 0.5 M of sodium methoxide in methanol. The mixture was heated to 160° C. for 12 min using a CEM Discover microwave reactor. The resultant solution was concentrated to ca. 10 ml, and 0.5 N HCl was added until a pH 3 was reached. The solution was extracted three times with ethyl acetate, and the organic fractions dried over sodium sulfate and concentrated to a tan solid; MS (−): m/z 337.14 (M−1)
Reaction SMILES: C([NH:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32](=[O:52])[C@H:33]([CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[NH:34][C:35]([O:37][CH3:38])=[O:36])[O:12][CH2:11]1)C1C=CC=CC=1.[H][H]>FC(F)(F)CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32](=[O:52])[C@H:33]([CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[NH:34][C:35]([O:37][CH3:38])=[O:36])[O:12][CH2:11]1
Reactant: [H][H]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: OCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of tert-butyl (2R,5R)-5-[(benzylamino)methyl]-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in 2,2,2-trifluoroethanol (0.17M) was added Pd(OH)2 (0.33 eq.). The reaction mixture was stirred for 16 hrs under one atmosphere of hydrogen. The reaction mixture was filtered on celite and the filtrate was concentrated under reduced pressure. The residue was used as such for the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:10]([O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(Cc2ccccc2)CCC1c1cccc(F)c1
Reactant: BrCc1ccc2ccccc2c1
Product: Fc1cccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)c1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating (3RS,4RS)-1-benzyl-4-(3-fluorophenyl)-piperidin-3-ol with 2-bromomethyinaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(3-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless oil; MS: 426 (M+H)+. By cleavage of the benzyl protecting group with 2,2,2-trichloroethyl chloroformate in an analogous manner to that described in Example 12 (c) there was obtained 2,2,2-trichloroethyl (3RS,4RS)-4-(3-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; MS: 510 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[N+:11]([O-])([O-:13])=[O:12].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]=1[OH:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCc1ccccc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 0 %

Procedure:
2-n-propylphenol (5.00 g, 36.8 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.43 g, 40.5 mmol). The addition of sulfuric acid (45 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(3.2 mg, 48%). 1H NMR (CD3COCD3): d 7.99 (d, 1H), 7.46 dd, 1H) 6.90 (t, 1H), 2.70 (t, 2H), 1.70 (m, 2H), 1.00 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>[Cu](I)I.CN(C=O)C>[CH3:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[N:7]=1
Reactant: Cc1ccc2c(Br)cccc2n1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1ccc2c(C#C[Si](C)(C)C)cccc2n1
Temperature: 110 °C
Yield: 90 %

Procedure:
In a sealed tube were introduced 5-bromo-2-methyl-quinoline (1.0 g, 4.5 mmol, 1.0 eq), PdCl2(PPh3)3 (154 mg, 0.22 mmol, 5% mol), copper iodide (42 mg, 0.22 mmol, 5% mol), and triphenylphosphine (236 mg, 0.9 mmol, 20% mol). Then, DMF (10 mL) was added followed by diethylamine (9.5 mL, 68 mmol, 15 eq) and trimethylsilylacetylene (700 μL, 5.0 mmol, 1.1 eq). The mixture was heated at 110° C. overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-EtOAc 95:5) to afford 2-methyl-5-trimethylsilanylethynyl-quinoline as a white solid (970 mg, 90%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[SH:11][CH2:12][CH2:13][S:14]([O-:17])(=[O:16])=[O:15].[Na+:18].CO.[Na]>CO>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([S:11][CH2:12][CH2:13][S:14]([O-:17])(=[O:16])=[O:15])=[N:7]2.[Na+:18]
Reactant: Clc1ccc2nccn2n1
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=S(=O)([O-])CCSc1ccc2nccn2n1
Yield: 80.1 %

Procedure:
To a solution of 1.35 g of 6-chloroimidazo[1,2-b]pyridazine in 30 ml of methanol were added 1.45 g of sodium 2-mercaptoethanesulfonate and 1.80 ml of 28 W/W % sodium-methanol solution, followed by refluxing for 5 hours. The precipitated crystals were collected by filtration and washed with methanol to obtain 1.98 g of sodium 2-[(imidazo[1,2-b]pyridazin-6-yl)thio]ethanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[CH2:24]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([F:10])[C:3]([C:11]2[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=2[F:21])=[C:2]([F:1])[CH:7]=1)[CH3:25]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(CO)cc2F)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a solution of methyl 6-(2,6-difluoro-4-(hydroxymethyl)phenyl)-5-fluoropicolinate (1.0 equiv.) in DMF (0.20 M) (colorless) at 0° C. was added sodium hydride (1.2 equiv.) and the reaction was stirred at 0° C. for 2 min. Ethyl iodide (1.2 equiv.) was added and the reaction was allowed to warm to room temperature. After 1 h, additional 1.0 equiv. of NaH was added and stirred for 15 ml. Reaction was quenched by the addition of sat. Ammonium chloride. The aqueous was acidified with conc HCl to pH3 and extracted with ethyl acetate three times. The organics were combined, dried with MgSO4, filtered and concentrated. The crude mixture was used as is. LC/MS=326.0 (MH+), Rt=0.94 min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.CS(O[CH:11]([CH3:16])[CH2:12][CH2:13][C:14]#[N:15])(=O)=O>C(O)C>[N:1]([CH:11]([CH3:16])[CH2:12][CH2:13][C:14]#[N:15])=[N+:2]=[N-:3]
Reactant: CC(CCC#N)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(CCC#N)N=[N+]=[N-]
Yield: 91.2 %

Procedure:
To a stirring solution of NaN3 (15 g) in boiling water (20 ml) was added a solution of crude 4-methanesulphonyloxypentanonitrile (37.7 g, ≈0.189 mol) in ethanol (240 ml) and the mixture refluxed for 1.5 h. After cooling the mixture was partitioned between H2O and CH2Cl2. The organic phase was dried and concentrated in vacuo to give 21.4 g of the title material as a light brown oil, (91.6): 1Hmr (CDCl3) δ: 4.05 (1H, q, J=13 Hz), 2.46 (2H, t, J=13 Hz), 1.8 (2H, t, J=13 Hz) and 1.35 ppm (3H, d, J=13 Hz); ir (neat) νmax : 2242, 2100 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[N+:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][S:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)(=[O:31])=[O:32])[CH:17]=1)=[CH:5]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol), was mixed with 3-nitrobenzenesulfonyl chloride (0.466 g, 2.0 mmol) and pyridine (9 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (15 mL) was added and the mixture allowed to stand 1.5 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL), and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a yellow solid. The solid was triturated with hexanes/ethyl acetate, 1/1, dried in vacuo, taken up in tetrahydrofuran, concentrated to dryness, triturated with hexanes/ethyl acetate, 4/1, v/v and was collected by filtration (0.488 g), mp 228-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6]/[C:13](/[CH3:15])=[CH:12]\[C:11]([O:17][CH3:18])=[O:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(Cl)cc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)/C=C(/C)Nc1c(C)cc(Cl)cc1C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a suspended solution of 4-chloro-2,6-dimethylaniline (24.0 g) in toluene (300 mL) were added methyl acetoacetate (17.9 g) and p-toluenesulfonic acid monohydrate (293 mg) and the mixture was heated to reflux and stirred for 4 hours. The reaction mixture was concentrated. To the obtained residue was added diisopropyl ether and the insoluble matter which was precipitated was removed. The filtrate was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography W-prep 2XY (column: main column 3L, inject column L; automatic condition setting: hexane:ethyl acetate=9:1, preparative isolation mode GR) to give the title compound (24.7 g) having the following physical data.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C@@H:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.[CH2:15](O)[CH3:16]>>[CH3:5][C@@H:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1
Reactant: C[C@@H]1CCN[C@@H](C(=O)O)C1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1C[C@H](C)CCN1
Reaction time: 1 h

Procedure:
Thionyl chloride (128.6 g) added dropwise to a stirred suspension of (2R,4R)-4-methyl-2-piperidinecarboxylic acid (51.6 g) in absolute ethyl alcohol (690 ml) below 30° C. and stirring continued for 1 hr. at room temperature and then for 1 hr. under reflux. After evaporation of the solvent, the residue was dissolved in benzene (500 ml), washed with 5% K2CO3 solution (100 ml) and saturated NaCl solution (200 ml), and dried over anhydrous Na2SO4. Upon evaporation of benzene, the residue was distillated in vacuo to give ethyl (2R,4R)-4-methyl-2-piperidinecarboxylate (57.4 g), b.p. 83°-5° C./7 mm Hg, [α]D22 =-24.0 (C=5 in EtOH), Analysis Calcd. for C9H17NO2 (percent): C, 63.13, H, 10.00, N, 8.18 Found (percent): C, 63.20, H, 9.96, N, 8.12.