Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[CH:37]=[CH:36][C:14]([CH2:15][C@@H:16]3[CH2:20][CH2:19][C@H:18]([C@H:21]([OH:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]3C(OC(C)(C)C)=O)=[CH:13][C:12]=2[Br:38])=[O:9])[N:6]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl.C(#N)C.O.CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[CH:37]=[CH:36][C:14]([CH2:15][C@@H:16]3[CH2:20][CH2:19][C@H:18]([C@H:21]([OH:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:17]3)=[CH:13][C:12]=2[Br:38])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(NC(=O)Cc3csc(N)n3)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(CC(=O)Nc2ccc(C[C@@H]3CC[C@H]([C@H](O)c4ccccc4)N3)cc2Br)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of 105 mg (0.175 mmol) of tert-butyl (2S,5R)-2-(4-{[(2-amino-1,3-thiazol-4-yl)acetyl]amino}-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (from Step A) in 2.0 mL DCM was added 1.0 mL TFA and the reaction mixture stirred at room temperature for 2 h. Azeotrop with toluene (2×) to excess acid. The residue was then taken up in acetonitrile/water/MeOH (9:1:1) and purified on the Gilson HPLC eluting with a 10-90% gradient of acetonitrile/water with 0.05% TFA buffer. The fractions containing the product were combined, frozen, and lyophilized to give a white foam (77 mg, 88%). m/z (ES) 501 (M)+ and 503 (M+2)+, also 523 (MNa)+ and 525 (MNa+2)+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:8]3=[C:7]([CH3:19])[C:6]=2[CH:5]=1.[Br:20]Br>>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:8]3=[C:7]([CH3:19])[C:6]=2[C:5]=1[Br:20]
Reactant: BrBr
Reactant: Cc1c2c(nc3ccc(N)cc13)CCCNC2
Agent: Cl
Product: Cc1c2c(nc3ccc(N)c(Br)c13)CCCNC2
Yield: 60 %

Procedure:
9-Amino-10-bromo-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline dihydrochloride was prepared from 9-amino-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline dihydrochloride by bromination with an equimolar quantity of bromine analogous to Example 148.
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)CCC.[F-].[Cs+]>CN(C=O)C.[Cu]I.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>[CH3:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:7][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1ccc(Br)c(C#N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccn2)c(C#N)n1
Temperature: 120 °C
Yield: 87.4 %

Procedure:
A mixture of 3-bromo-6-methylpicolinonitrile (1 g, 5.1 mmol), 2-(tributylstannyl)pyridine (2.43 ml, 6.60 mmol), cesium fluoride (150 mg, 10.2 mmol), CuI (193 mg, 1.02 mmol) and Pd(PPh3)4 (586 mg, 0.51 mmol) in DMF (10 mL) was degassed and heated at 120° C. for 1 h in a microwave reactor. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% DCM/EtOAc) to yield the title compound as a brown oil (0.87 g, 88%). MS (ESI) 196 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N+:9]([O-])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>P(OCC)(OCC)OCC>[C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][n+]1cnnc(-c2ccccc2)c1
Agent: CCOP(OCC)OCC
Product: c1ccc(-c2cncnn2)cc1
Yield: 77.6 %

Procedure:
A mixture of 6-phenyl-[1,2,4]triazine-4-oxide (27 g, 156 mmol) and triethyl phosphite (500 ml) was heated under reflux for 30 min. The cooled reaction mixture was evaporated tit vacuo and the residue was purified by flash chromatography (SiO2; 50% Et2O in hexanes) to afford 19 g (121 mmol, 78%) of 6-phenyl-[1,2,4]triazine as a yellow solid. δH (400 MHz; CDCl3) 7.56-7.59 (3H, m, aromatics), 8.10-8.14 (2H, m, aromatics), 9.03 (1H, s, triazine H5), 9.65 (1H, s, triazine H3); m/z (ES+) 158 (M++H, 100%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C:32]([F:35])([F:34])[F:33])=[N+]=[N-].C(Cl)CCl.[C:49]([N:56]1[CH2:63][CH2:62][CH2:61][C@H:57]1[C:58](O)=[O:59])([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C1C=NC2N(O)N=NC=2C=1>O.CN(C=O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([CH:31]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:32]([F:35])([F:34])[F:33])=[C:24]([CH:29]=1)[CH2:23][NH:20][C:58](=[O:59])[C@@H:57]1[CH2:61][CH2:62][CH2:63][N:56]1[C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)(F)F)cc1
Agent: On1nnc2cccnc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (0.157 mg, 0.60 mmol) was added to a stirred solution of N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.199 mg, 0.538 mmol) in water (1 mL) and water (30 μL). After 16 h the volatiles were evaporated in vacuo, the residue was dissolved in methanol (1 mL), potassium hydroxide (1 pellet) was added and the mixture was stirred at 60° C. for 15 min. The reaction mixture was then cooled and partitioned between ether and water. The organic layer was dried (Na2SO4) and evaporated to a gum. EDC (154.7 mg, 0.81 mmol) was added to a stirred mixture of this crude amine, N-Boc-L-proline (115.8 mg, 0.54 mmol) and HOAT (36.6 mg, 0.27 mmol) in DMF (3 mL). After 16 h, the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography on silica gel (eluting with EtOAc/CHCl3, 1:5) to give N-(5-chloro-2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (196 m g) as a glass: MS: 542.3 (M+1).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[P:22]([O-:28])([O:26][CH3:27])([O:24][CH3:25])=[O:23].[K+].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[CH3:25][O:24][P:22](=[O:23])([O:26][CH3:27])[O:28][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CCl
Reactant: COP(=O)([O-])OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COP(=O)(OC)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 0 °C
Yield: 41.1 %

Procedure:
Thirty grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 17.1 g of potassium dimethyl phosphate, 0.6 g of potassium carbonate, and 0.15 g of potassium iodide were slurried into 75 mL of acetonitrile. The reaction mixture was heated at reflux for 3 hours. The solution was filtered to remove potassium chloride precipitate and concentrated to thick oil. Isopropyl alcohol was added to the oil and cooled to 0° C. The product was filtered and dried under vacuum. Sixteen grams of the title compound was obtained (40.9% yield); mp 123.1-124.3° C. Proton nuclear magnetic resonance spectroscopy (1H NMR) deuterated dimethyl sulfoxide (DMSO-d6): 3.6 ppm (d, 6H), 5.3 (d, 2H), 7.3-7.5 (m, 10H), 10.0 (s, 1H); doublets from long range phosphorous coupling.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]([CH3:24])=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:5])[CH3:2].[Na].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]([CH3:24])=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:27][CH:29]2[O:31][CH2:30]2)=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(C)c(C(=O)OCC)c1-c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(C)c(C(=O)OCC)c1-c1ccc(OCC2CO2)cc1

Procedure:
9.0 g of the resulting 2,6-dimethyl-4-(4-hydroxyphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester are dissolved in a solution prepared from 0.723 g of sodium metal and 80 ml of ethanol. This solution is slowly added drop-wise to a boiling solution of 11.9 ml of epichlorohydrin in 80 ml of ethanol; after cooling, the sodium chloride that is deposited is filtered off with suction and the filtrate is concentrated to dryness by evaporation. The residue is dissolved in ether and washed in succession with aqueous 1N sodium hydroxide solution, 1N hydrochloric acid, saturated aqueous potassium bicarbonate solution and finally with water. After distilling off the ether, the crude 2,6-dimethyl-4-[4-(2,3-epoxypropoxy)-phenyl]-pyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH2:25][CH:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH3:27])[C:21]([Cl:33])=[CH:20][N:19]=1>>[Cl:33][C:21]1[C:22]([NH:24][CH2:25][CH:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH3:27])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NCC(C)NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-1-methyl-ethyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1-methyl-ethyl]-methanesulfonamide in an analogous manner to Example 300. Product isolated as a white solid (96 mg, 58%). LCMS (m/e) 483 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.35-7.23 (m, 2H), 7.05 (d, 1H, J=8.0 Hz), 6.93 (s, 1H), 5.70-5.62 (m, 1H), 5.40-5.31 (m, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.53-3.43 (m, 1H), 3.39 (s, 3H), 2.97-2.87 (m, 4H) 2.90 (s, 3H), 2.80-2.69 (m, 6H), 1.31 (d, 3H, J=6.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
A mixture of piperazine-1-carboxylic acid tert-butyl ester (18.6 g, 0.1 mol), 4-fluoro-benzoic acid ethyl ester (16.8 g, 1 mol) and potassium carbonate (0.15 mol) in dimethylsulfoxide (100 mL) was stirred at 120° C. for 24 h. The reaction mixture was cooled to room temperature and poured into water (1 L). The solid precipitate was filtered, washed with water, and concentrated to dryness to provide the title compound (20 g, 60% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.91 (d, 2H), 6.83 (d, 2H), 4.30 (q, 2H), 3.55 (m, 4H), 3.26 (m, 4H), 1.46 (s, 9H), 1.32 (t, 3H).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:30]C1C(C)=CC=CC=1N1CCNCC1>>[CH3:30][C:4]1[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18]2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: Cc1cccc(N2CCN(CCn3cnc4ccccc4c3=O)CC2)c1C

Procedure:
This compound was prepared in compliance with the procedure described in 1c, using 1-(2,3-dimethylphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [Si](O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)CNCCCCCCCCNC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)(C(C)(C)C)(C)C.[NH2:67][CH2:68][C@@H:69]([C:78]1[C:83]2[O:84][CH2:85][C:86](=[O:88])[NH:87][C:82]=2[CH:81]=[C:80]([OH:89])[CH:79]=1)[O:70][Si:71]([C:74]([CH3:77])([CH3:76])[CH3:75])([CH3:73])[CH3:72].[CH3:90][O:91][C:92]1[CH:93]=[C:94]([NH:98][C:99]2[C:108]3[C:103](=[C:104]([CH3:124])[CH:105]=[C:106]([S:109]([CH2:112][CH2:113][CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH:122]=O)(=[O:111])=[O:110])[CH:107]=3)[N:102]=[CH:101][C:100]=2[C:125]([NH2:127])=[O:126])[CH:95]=[CH:96][CH:97]=1>>[Si:71]([O:70][C@H:69]([C:78]1[C:83]2[O:84][CH2:85][C:86](=[O:88])[NH:87][C:82]=2[CH:81]=[C:80]([OH:89])[CH:79]=1)[CH2:68][NH:67][CH2:122][CH2:121][CH2:120][CH2:119][CH2:118][CH2:117][CH2:116][CH2:115][CH2:114][CH2:113][CH2:112][S:109]([C:106]1[CH:107]=[C:108]2[C:103](=[C:104]([CH3:124])[CH:105]=1)[N:102]=[CH:101][C:100]([C:125]([NH2:127])=[O:126])=[C:99]2[NH:98][C:94]1[CH:95]=[CH:96][CH:97]=[C:92]([O:91][CH3:90])[CH:93]=1)(=[O:111])=[O:110])([C:74]([CH3:77])([CH3:75])[CH3:76])([CH3:73])[CH3:72]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1cc(O)cc2c1OCC(=O)N2
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCC=O)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c4cc(O)cc5c4OCC(=O)N5)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 148, using (R)-8-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one in place of Intermediate 2 and Intermediate 126 in place of Intermediate 112. ES/MS calcd. for C45H64N5O8SSi+ 862.4. Found m/z=862.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[C:34]1([O:33][C:31](=[O:32])[NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
The 4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (2.96 g, 10.0 mmol) obtained by the method described in W097/17329 and triethylamine (1.21 g, 12.0 mmol) were dissolved in dimethylformamide (30 ml), and after adding phenyl chloroformate (1.72 g, 11.0 mmol) while cooling on ice, the mixture was stirred at room temperature for 1 hour. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=3:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (2.50 g, 6.00 mmol, 60%) as colorless crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[C:12]([NH:14][NH2:15])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[N:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1>C(O)CCC>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]2[N:14]([C:12]([CH:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[CH3:16])=[N:20][N:19]=2)[N:15]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(C(=O)NN)c1ccc2ncccc2c1
Solvent: CCCCO
Product: Cc1ccc2nnc(C(C)c3ccc4ncccc4c3)n2n1
Temperature: 120 °C
Yield: 53 %

Procedure:
2-Quinolin-6-yl-propionic acid hydrazide (intermediate 63) (500 mg, 2.32 mmol) was added to a stirred solution of 3-chloro-6-methylpyridazine (299 mg, 2.32 mmol) in n-butanol. The reaction mixture was heated at 120° C., overnight. The volatiles were removed in vacuo and the residue absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to obtain 6-[1-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (356 mg, 53% yield). To 6-[1-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (356 mg, 1.23 mmol) was added a dropwise solution of bromine (1.73 uL, 3.69 mmol) in acetic acid (3 mL). The reaction was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. A solution of 10% aq. NaSH (10 mL) was added and the product extracted with 10% methanol in dichloromethane. The organic phase was washed with 5% aqueous sodium sulfite. The filtrate was then concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (168 mg, 37% yield). Analytical data presented in Table 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].C(N(C(C)C)C(C)C)C.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>C(Cl)Cl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: COC[C@H](C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
(1S)-2-Methoxy-1-methylethylamine (7.34 g, 82.4 mmol) and N-ethyl-N,N-diisopropylamine (19.1, 110 mmol) was added dropwise over 20 min to a cooled (0° C.) solution of 4-bromobenzenesulfonyl chloride (14.0 g, 55 mmol) in methylene chloride (200 mL). The reaction mixture was allowed to stir for 1 h. Water was added and the mixture was washed, twice, with HCl (1 M) and once with saturated aqueous sodium hydrogen carbonate. The organic phase was dried over sodium sulfate and evaporated to give 15.1 g, (94% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.76 (d, J=8 Hz, 2H), 7.65 (d, J=8 Hz, 2H), 4.97 (m, 1H), 3.46 (m, 1H), 3.23 (m, 5H), 1.12 (d, J=7 Hz, 3H); MS (ESI) m/z 308 and 310 (M++1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[N:10]1.[C:14]([Cu])#[N:15]>CN1C(=O)CCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[C:3]([N:9]2[CH:13]=[CH:12][N:11]=[N:10]2)[CH:4]=1
Reactant: Fc1ccc(Br)c(-n2ccnn2)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(F)cc1-n1ccnn1
Yield: 60.8 %

Procedure:
A mixture of 1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole (0.603 g, 2.49 mmol), CuCN (0.245 g, 2.74 mmol), and 15 mL of NMP was subjected to microwave irradiation at 150° C. for 0.5 h. The brown mixture was filtered over celite and washed with dimethylfomamide. This solution was treated with 10% aqueous NH4OH (28-30% solution) and extracted with ethyl acetate. The combined organic layers were successively washed with 10% aqueous NH4OH (28-30% solution), sat. NH4Cl aq., water, brine and dried over Na2SO4. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage system on silica gel with hexanes:ethyl acetate (7:3 to 6:4) gradient as the eluent to afford the title compound as a light yellow solid (0.285 g, 61% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 8.40 (1 H, d, J=1.0 Hz), 7.96 (1 H, s), 7.91 (1 H, dd, J=8.6, 5.6 Hz), 7.77 (1 H, dd, J=8.7, 2.4 Hz), 7.31-7.39 (1 H, m).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[CH:8]1(CC(O)=O)[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH:13]=[CH:12][CH:11]=[C:10]3C1.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.C(Cl)Cl>[CH:7]1([CH2:6][NH2:3])[C:10]2=[C:19]3[C:14](=[CH:13][CH:12]=[CH:11]2)[CH:15]=[CH:16][CH:17]=[C:18]3[CH2:8]1
Reactant: CCN(CC)CC
Reactant: O=C(O)CC1Cc2cccc3cccc1c23
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: NCC1Cc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 250 ml three-necked flask, triethylamine (3.49 ml, 2.50.10−2 mol, 1.15 eq.) is added dropwise to a solution, cooled to 0° C., of the acid obtained in Step D (4.62 g, 2.18. 10−2 mol) in a mixture of acetone (95 ml) and water (5.4 ml). Ethyl chloroformate (2.71 ml, 2.83.10−2 mol, 1.30 eq.) is then slowly added at 0° C.; evolution of gas is visible. The mixture is stirred at 0° C. for 30 minutes; after it has been established, on TLC (CH2Cl2), that the starting material has disappeared, a solution of sodium azide (1.89 g, 2.83.10−2 mol, 1.30 eq.) in water (9.2 ml) is added at 0° C. The mixture is maintained at that temperature for one hour. The mixture is poured into an ice/water mixture and is then extracted with ether. The ethereal phases are washed with water, then dried over Na2SO4 and evaporated in vacuo without heating. The acyl azide is taken up in 50 ml of anhydrous toluene and then heated at 80° C. until nitrogen is no longer evolved. After evaporating off the toluene, the oil corresponding to the isocyanate is heated at 100° C. together with a 20% hydrochloric acid solution (52 ml) for 3 hours; the mixture is stirred for one night at ambient temperature. The reaction mixture is diluted with water, filtered through filter paper and extracted with ether. The aqueous phase of pH=1 is rendered basic using solid sodium carbonate and is then extracted three times with dichloromethane. The combined organic phases are washed with water and dried over K2CO3. After evaporating off the solvent under reduced pressure, the amine is obtained in the form of an oil (820 mg). The solid, having been filtered and taken up in dichloromethane, is treated in the same manner as the filtrate. The amine so obtained is converted into the hydrochloride after being solubilised in ether and treated with a 4N ethereal hydrogen chloride solution. After drying, the title product is obtained in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH:10]=C(C#N)[C:8]=2[CH:20]=1)([O-:3])=[O:2].[C:21]([OH:24])(=[O:23])[CH3:22].S(=O)(=O)(O)O>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH:10]=[C:22]([C:21]([OH:24])=[O:23])[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: N#CC1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
A mixture of 0.13 g of 6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carbonitrile, 10 ml of acetic acid, 5 ml of water and 5 ml of concentrated sulfuric acid was refluxed with heating for 2 hours. When the reaction mixture was poured into ice water, crystals were separated out. The crystals were dissolved into a sodium hydrogencarbonate solution and washed with methylene chloride. A water layer was acidified to be hydrochloric acid and extracted with methylene chloride. After an organic layer was washed with water and dried, the solvent was distilled. The resultant residue was crystallized by a mixed solvent of ethyl acetate and methanol to obtain 55 mg of 6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carboxylic acid with a melting point of 259°-261° C.