Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](CC)=O.C(=O)([O-])[O-].[K+].[K+].C(I)C.[OH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH2:20][C:19]2=[O:30]>>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:28])([CH3:29])[CH2:20][C:19]2=[O:30])[CH3:2]
Reactant: CCC(C)=O
Reactant: COc1cc2c(cc1O)C(=O)CC(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCOc1cc2c(cc1OC)OC(C)(C)CC2=O
Yield: 95 %

Procedure:
In 100 ml of methyl-ethyl-ketone 4.45g (20 millimoles) of 6-hydroxy-7-methoxy-2,2-dimethy-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.7 g (2.4 ml, 30 millimoles) of ethyl iodide are added and the reaction mixture is refluxed for 5 hours. The precipitated inorganic salt is filtered off, washed twice with 20 ml of acetone each and the solvent is removed. The residue is crystallized from 90% ethanol. Thus 4.75 g of the desired compound are obtained, yield 95%. Mp.: 86°-87° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[NH2:26][CH2:27][CH2:28]O.B(F)(F)F>O1CCCC1>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)[NH:26][CH2:27][CH2:28]1
Reactant: NCCO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NCCO4)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), 2-aminoethanol (1.0 mmol) and BF3.etherate (2.0 mmol) in tetrahydrofuran (10 ml) at a temperature 65° C. for 6 hours in 78% yield.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].CN([CH2:9][C:10]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][CH:11]=1)C.COS(OC)(=O)=O>CCO>[N+:19]([C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[NH:12][CH:11]=[C:10]2[CH2:9][CH:4]([N+:1]([O-:3])=[O:2])[CH3:5])([O-:21])=[O:20]
Reactant: CC[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: CCO
Solvent: COS(=O)(=O)OC
Product: CC(Cc1c[nH]c2ccc([N+](=O)[O-])cc12)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 0.3 g (0.013 mole) of Na in 65 ml of abs EtOH was added 2.93 g (0.039 mole) of nitroethane dropwise. To the white suspension was added 2.19 g (0.01 mole) of 5-nitrogramine suspended in 40 ml of abs EtOH, followed by 2.5 g (0.02 mole) of dimethylsulfate in 20 ml of abs EtOH dropwise over 15 minutes. The mixture was stirred for 2 hours, then poured into 350 ml of ice water. The yellow solid was filtered, washed with ice water and air-dried to give 1.63 g (64%) of product: m.p. 130-131.5.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[CH2:30][CH2:31][C:32]#[N:33]>C(Cl)Cl>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:30][CH2:31][C:32]#[N:33])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(C(c2ccccn2)N2CCNCC2)cc1
Reactant: N#CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CCCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
1.05 g of N,N-diisopropyl-N-ethylamine was added, with stirring, to a solution of 2.0 g of 4-[α-(2-pyridyl)benzyl]piperazine and 1.0 g of 3-bromopropionitrile in 20 ml of methylene chloride, whilst ice-cooling, and the mixture was stirred at room temperature for 16 hours. At the end of this time, the mixture was poured into ice-water and extracted with chloroform. The extracts were combined and dried over anhydrous sodium sulfate, after which the solvent as removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 2:1 g (yield 88%) of the title compound as crystals, melting at 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=C([CH:13]=[CH:14][CH:15]=2)C#N)=[O:7])=[CH:4][CH:3]=1.[C:18]([OH:21])(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:19]([CH:13]=[CH:14][CH:15]=2)[C:18]([OH:21])=[O:20])=[O:7])=[CH:16][CH:17]=1
Reactant: N#Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 10 °C

Procedure:
46.5 g of 3-p-chlorobenzoyl benzonitrile were added to a mixture of 350 cc of water, 350 cc of glacial acetic acid and 350 cc of concentrated sulfuric acid and the resulting mixture was refluxed for 3 hours and 40 minutes. After cooling to 10° C., the mixture was slowly added to water and the precipitate formed was recovered by vacuum filtration, was washed and dried to obtain 48 g of 3-p-chlorobenzoyl benzoic acid melting at 228° C. A sample of the product after crystallization from acetone melted at 234° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:5][N:4]([C:6]([C@@H:8]2[CH2:12][C@H:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[C:23]([F:26])([F:25])[F:24])(=[O:15])=[O:14])[CH2:10][C@H:9]2[C:27]([OH:29])=O)=[O:7])[CH2:3]1.[CH2:31]1[C:33]([NH2:36])([C:34]#[N:35])[CH2:32]1.Cl>>[C:34]([C:33]1([NH:36][C:27]([C@@H:9]2[CH2:10][C@@H:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[C:23]([F:24])([F:26])[F:25])(=[O:15])=[O:14])[CH2:12][C@H:8]2[C:6]([N:4]2[CH2:5][C:2]([F:30])([F:1])[CH2:3]2)=[O:7])=[O:29])[CH2:31][CH2:32]1)#[N:35]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)C[C@H]1C(=O)N1CC(F)(F)C1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 117, step 7, using (1R,2R,4S)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid and 1-amino-cyclopropyl cyanic hydrochloride. White solid. MS (EI): 524.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1.[NH:17]1[CH:24]=[CH:23][C:21]([NH2:22])=[N:20][C:18]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:22][C:21]1[CH:23]=[CH:24][N:17]([CH2:2][C:3]2[O:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=2)[C:18](=[O:19])[N:20]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2ccc(-c3ccccc3[N+](=O)[O-])o2)c(=O)n1
Reaction time: 12 h
Yield: 66.8 %

Procedure:
To a solution of 2-(bromomethyl)-5-(2-nitrophenyl)furan 11a (230 mg, 0.815 mmol) and cytosine 14a (181 mg, 1.63 mmol) in anhydrous DMF (4 mL) was added cesium carbonate (398 mg, 1.22 mmol) at 25° C. The resulting solution was stirred for 12 h at the same temperature. After removal of the DMF under reduced pressure, the residue was diluted with CHCl3 and washed three times with water. The organic layer was dried over anhydrous MgSO4 and concentrated in a vacuum. The residue was purified by column chromatography eluting with ethyl acetate/methanol (20:1) to afford 170 mg (67%) of the cytosine 15a as a white solid. 1H NMR (DMSO) δ: 7.87 (1H, d, J=8.0 Hz), 7.82 (1H, d, J=7.5 Hz), 7.73 (1H, t, J=7.5 Hz), 7.58 (1H, d, J=7.0 Hz), 7.56 (1H, t, J=8.5 Hz), 7.16 (1H, s), 7.09 (1H, s), 6.86 (1H, d, J=3.5 Hz), 6.48 (1H, d, J=3.0 Hz), 5.72 (1H, d, J=7.5 Hz), 4.89 (2H, s); 13C NMR δ: 166.33, 155.63, 152.62, 147.82, 147.11, 145.59, 132.72, 129.41, 128.80, 124.16, 122.73, 110.07, 110.92, 94.21, 44.57.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)nc1
Reaction time: 48 h
Yield: 67.9 %

Procedure:
To a solution of 6-chloropyridin-3-ol (40 g, 309 mmol, Eq: 1.00) and ethyl 2-bromo-2-methylpropanoate (63.2 g, 48.1 ml, 324 mmol, Eq: 1.05) in 300 ml of CH3 CN was added Cs2 CO3 (216 g, 664 mmol, 309 mmol, Eq: 2.15) and the resulting reaction mixture was stirred under argon atmosphere for 48 h. The reaction mixture was filtered and the filtercake was washed well with EtOAc. The combined filtrate and washes were diluted with water (300 ml) and shaken and the organic phase was collected. The aqueous phase was back-extracted with EtOAc (2×150 ml). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by passing through a plug of 200 g of silica and elution with 30% EtOAc/Hexanes afforded the desired product (51.1 g) as a light yellow oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.18 Hz, 3 H) 1.61 (s, 6 H) 4.24 (q, J=7.18 Hz, 2 H) 7.12-7.25 (m, 2 H) 8.01 (d, J=2.64 Hz, 1 H).
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]34[O:26][C:17]3([C:18](=[O:27])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:28][CH3:29])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:31]=[CH:32][C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36].C(N)CCC>[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:31]=[CH:32]\[C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]34[O:26][C:17]3([C:18](=[O:27])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:28][CH3:29])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2ccc(OC)cc2C23OC12CCCC3=O
Reactant: C[Si](C)(C)C#CC=CCl
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: COc1ccc2c(c1)C13OC1(CCCC3=O)C(C#C/C=C\C#C[Si](C)(C)C)N2C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A solution of Compound 314 (5.69 g, 14.6 mmol) in dry degassed benzene (120 mL) was added to copper (I) iodide (0.666 g, 3.51 mmol), and to the resulting mixture was added 1-chloro-4-(trimethylsilyl)-but-1-en-3-yne (3.69 g, 23.4 mmol) followed by n-butylamine (2.89 mL, 29.2 mmol) and tetrakis(triphenylphosphine) palladium (0) (1.01 g, 0.877 mmol) in dry degassed benzene (60 mL). The reaction mixture was stirred at 25° C. for 2 hours, diluted with ethyl ether (200 mL), poured into saturated aqueous ammonium chloride (200 mL), and extracted with ethyl ether (2×70 mL). The combined organic layers were dried (MgSO4 )and evaporated in vacuo. The residue was purified by flash column chromatography (silica, 25 percent ethyl ether in petroleum ether) to give 5.43 g (73 percent) of Compound 315: white foam; Rf =0.29 (silica, 30 percent ethyl ether in petroleum ether); IR (CHCL 3) νmax 2958, 2836, 1717, 1609, 1590, 1493, 1380, 1299, 1251 cm-1 ; 1H NMR (300 MHz, CDCl3) δ7.94 (d, J=3.0 Hz, 1 H, aromatic), 7.38-7.06 (m, 6 H, aromatic), 6.89 (dd, J=8.9, 3.0 Hz, 1 H, aromatic), 5.92 (d, J=1.6 Hz, 1 H, H6), 5.86 (d, J=11.0 Hz, 1 H, olefinic), 5.65 (br d, J=11.0 Hz, 1 H, olefinic), 3.81 (s, 3 H, OCH 3), 2.78-2.62 (m, 2 H, H9), 2.37-2.25 (m, 2 H, H7), 2.05-1.85 (m, 2 H, H8), 0.20 (s, 9 H, Si(CH3)3) ;13C NMR (125 MHz, CDCl3) δ201.2, 157.2, 154.1, 151.0, 129.3, 128.6, 128.5, 125.7, 124.0, 121.4, 120.7, 118.9, 114.8, 114.8, 103.5, 101.5, 90.5, 83.0, 74.6, 57.4, 55.4, 48.4, 38.8, 23.8, 18.2, -0.17; MS (FAB+) m/e (rel intensity) 511 (M+, 100), 390 (8), 362 (9), 176 (11), 120 (10); HRMS for C30H29NO5Si (M+) , calcd 511.1815, found 511.1815.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH2:11][CH3:12])[CH2:14][C:15]([OH:20])([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:16]([F:18])([F:17])[F:19])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 11 from 2-chlorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH:5][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1cc(F)cc(F)c1)OCc1ccccc1
Reaction time: 16 h
Yield: 93.8 %

Procedure:
3,5-Difluoroaniline (4.89 g, 37 91 mM) in acetone (130 ml) and water (70 ml) at 0° C. was treated with sodium hydrogen carbonate (6.55 g, 78.0 mM) and then benzyl chloroformate (6.67 g, 5.6 ml, 39.23 mM) over 10 min. The mixture was stirred for 16 h and then poured into ice. The resultant precipitate was collected and washed with water to give the title carbamate (9.35 g, 94%);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([OH:26])[CH2:16][C:17]#[C:18][Si](CC)(CC)CC)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:28]1[CH:34]=[C:33]([N:35]2[CH:39]=[N:38][N:37]=[CH:36]2)[CH:32]=[CH:31][C:29]=1[NH2:30]>>[N:37]1[N:38]=[CH:39][N:35]([C:33]2[CH:32]=[C:31]3[C:29](=[CH:28][CH:34]=2)[NH:30][CH:18]=[C:17]3[CH2:16][CH:15]([OH:26])[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:36]=1
Reactant: Nc1ccc(-n2cnnc2)cc1I
Reactant: CC[Si](C#CCC(O)CC1CCN(C(=O)OC(C)(C)C)CC1)(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(O)Cc2c[nH]c3ccc(-n4cnnc4)cc23)CC1

Procedure:
Prepared according to the procedure described for Example 49 step d, using (±)-5-[N-(tert-butyloxycarbonyl)piperidin-4-yl]-4-hydroxy-1-triethylsilyl-1-pentyne (Example 49, step b) and 2-iodo-4-(1,2,4-triazol-4-yl)aniline. 1H NMR (250 MHz, CDCl3) δ 1.04-1.19 (3H, m), 1.44 (9H, s), 1.68 (4H, m), 2.69 (2H, bt), 2.82 (1H, dd), 3.0 (1H, dd), 4.08 (3H, m), 7.17 (1H, dd), 7.25 (2H, m), 7.50 (1H, d), 7.59 (1H, d), 8.44 (2H, s), 8.46 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[CH:40]([N:43]=[C:44]=[S:45])([CH3:42])[CH3:41]>C(#N)C>[CH:40]([NH:43][C:44]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:3]2[N:4]=[C:5]3[N:11]([CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[CH:6]3[O:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:2]=2[CH3:1])=[CH:25][CH:26]=1)=[S:45])([CH3:42])[CH3:41]
Reactant: CC(C)N=C=S
Reactant: Cc1c(-c2ccc(N)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(NC(=S)NC(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-[1-methyl-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 173) (50 mg, 0.124 mmole) in ACN (1 mL) are added DIEA (65 μL, 0.372 mmole) and isopropylisothiocyanate (18.8 mg, 0.182 mmole). The reaction mixture is heated overnight at 80° C. Solvent is removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH:NH4OH) from (98:2:02) to (96.5:3.5:0.35) to give 1-isopropyl-3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diazabenzo[f]azulen-2-yl]-phenyl}-thiourea. [M+H]+=504.37.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=[C:15]3[N:16]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)C.O>[N:9]1([C:12]2[N:16]=[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[N:13]=2)[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCN(c2nc3cccccc-3n2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc2nc(N3CCNCC3)nc-2cc1
Yield: 126.2 %

Procedure:
A mixture of 4-(2-cycloheptimidazolyl)-piperazine-1-carboxylic acid ethyl ester (2.86 g, described in Example 1) and potassium hydroxide in ethanol (20 ml) and water (1.5 ml) was refluxed for 20 hr. Water was added and the ethanol was evaporated. Additional water was added and the solution was extracted with chloroform. The organic extract was dried and evaporated to give the title compound (2.7 g). To a solution of the title compound in chloroform and diethyl ether, a solution of hydrogen chloride in diethyl ether was added. The precipitate was collected and crystallized from methanol-diethyl ether to obtain the hydrochloride salt of the title compound (2.4 g): mp>280° C.; ir(nujol) 2600, 1630 and 1584 cm-1 ; uv max (MeOH) 285(ε7540), 261(ε26,930) and 236 nm(ε18,310) and nmr(DMSO-d6)δ 3.37(4H,t), 4.3(4H,t), 8.4(5H,m) and 10.0(2H,s).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:36]1[C:45]2[C:44](=[O:46])[NH:43][CH:42]=[CH:41][C:40]=2[CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:43]4[C:44](=[O:46])[C:45]5[N:36]=[CH:37][CH:38]=[CH:39][C:40]=5[CH:41]=[CH:42]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: O=c1[nH]ccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ccc5cccnc5c4=O)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A suspension of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (27.0 mg, 0.051 mmol), 1,7-naphthyridin-8(7H)-one (22.4 mg, 0.153 mmol) and Cs2CO3 (66.5 mg, 0.204 mmol) in anhydrous DMF (1.0 mL) was heated in a microwave at 150° C. for 50 min. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 90% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H32ClN4O4S: 639.2; found: 639.3.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(COS(C)(=O)=O)cn1
Reaction time: 0.5 h

Procedure:
To a solution of (6-Methyl-pyridin-3-yl)-methanol (24.36 kg, 198 mol) dissolved in tetrahydrofuran (80 kg) under nitrogen at −3° C. was added triethylamine (22.14 kg, 218.8 mol) over 30 mins followed by methanesulphonyl chloride (23.16 kg, 202.2 mol) over 3 hr and the slurry stirred for an additional 30 mins. The slurry was then filtered to remove triethylamine hydrochloride and the cake washed four times with tetraydrofuran (21.6 kg). An aliquot was removed and concentrated and analysed.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CN(C)CCN
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Product: CN(C)CCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 60 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
0.098 g (0.00025 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 3 ml of dioxane and treated with 0.27 ml of 2dimethylaminoethylamine. The mixture was stirred at 60° C. for 48 hrs., the solvent was removed and the residue was chromatographed on silica gel with 2% methanol in dichloromethane. There was obtained 0.084 g (84%) of N-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-N',N'-dimethylethane-1,2-diamine as a light yellow, amorphous solid. MS (ISP): me/e =401, 399 (C15H20BrN4O2S+).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].[NH3:21]>O>[NH2:21][C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20]
Reactant: N
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Solvent: O
Product: CCCN1CC(C)=C(N)C2=C1N1CN(OC)C=C1C=N2
Temperature: 130 °C

Procedure:
10 g of intermediate A1 and 200 ml of an aqueous solution of NH3 (32%) are mixed in an autoclave and heated up to 130° C. for 8 hours. The reaction mixture is diluted with 200 ml water. The precipitated reaction product is separated washed with water and dichloro methane and dried at reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([F:38])[C:31]=1[CH2:39][CH:40]([NH2:42])[CH3:41]>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:42][CH:40]([CH3:41])[CH2:39][C:31]4[C:32]([F:38])=[C:33]([F:37])[CH:34]=[C:35]([F:36])[C:30]=4[F:29])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Solvent: CCCCO
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Yield: 42.8 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.54 g, 1.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.34 g, 1.62 mmol), Hunig,s base (0.87 g, 6.75 mmol), and 12 mL of anhydrous 1-butanol was heated at reflux for 13-14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.33 g of the designed compound as yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.33 (s, 1H, NH), 11.29 (br s, 1H, NH), 11.00 (d, J=5.7 Hz, 1H, NH), 7.97 (s, ArH), 7.73-7.70 (m, 1H, ArH), 7.40 (d, J=7.6 Hz, 1H, ArH), 6.21 (d, J=7.6 Hz, 1H, ArH), 4.32-4.28 (m, 1H, CH), 3.65 (t, J=6.3 Hz, 2H, CH2), 3.08 (d, J=5.1 Hz, 2H, CH2), 2.72 (s, 3H, CH3), 2.19 (S, 6H, 2×CH3); 1.36 (d, J=6.3 Hz, 3H, CH3), 1.11 (t, J=6.3 Hz, 2H, CH2); Mass (ESI, negative) m/z 568.8 [M−H]−.