Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])=[O:5].N1C=CC=CC=1.[F:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1>[F:28][CH2:29][C:30]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:31]
Reactant: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)CF
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 91.2 %

Procedure:
3.3 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-4-chloroaniline and 1.6 g of pyridine are dissolved in 60 ml of tetrahydrofuran, and 1.93 g of fluoroacetyl chloride are added dropwise thereto under ice-cooling and stirring. The mixture is stirred for 30 minutes under ice-cooling and further stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure to remove tetrahydrofuran. Water is added to the residue and crystalline precipitates are collected therefrom. The crystals are recrystallized from a mixture of dimethylformamide and ethanol (1:3). 3.6 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-chloroaniline are obtained as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[C@H:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:32])[CH2:23][CH2:24]3)[C:5]([C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: OCCCNc1nc(Cl)ccc1C(F)(F)F
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a solution of 3-{[6-chloro-3-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 302) (0.63 g, 2.45 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.45 g, 2.05 mmol) in THF (6.80 mL) was added triphenylphosphine (0.70 g, 2.66 mmol) and 1,1′-azodicarbonyl)-dipiperidine (0.68 g, 2.66 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.58 g, 62%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.65 (d, 1H), 7.02 (d, 1H), 6.76 (d, 1H), 6.69 (dd, 1H), 6.60 (d, 1H), 6.48 (b, 1H), 4.15 (q, 2H), 4.04 (t, 2H), 3.65 (q, 2H), 3.46 (qt. 1H), 2.92-2.68 (m, 3H), 2.42-2.30 (m, 2H), 1.78-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[C:11]([Br:14])[CH:12]=2)[N:7]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH:6]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(Cl)c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromo-6-chloro-1H-indole-3-carboxylic acid methyl ester (80.0 g, 277 mmol) in N,N-dimethylformamide (600 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 16.6 g, 416 mmol) portion-wise over 20 minutes. The reaction was stirred at 0° C. for 60 minutes followed by the addition of 4-methylbenzenesulphonyl chloride (63.4 g, 333 mmol), which was added portion-wise to the stirring solution. The reaction was allowed to stir for 2 hours at 0° C. and the ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into water (1200 mL) and stirred for 12 hours. The suspension was filtered and the filter cake was washed with a further portion of water (700 mL) then heptane (2×300 mL), 160 g of crude material was recovered. The material was placed in a 3 L round bottom flask and placed on rotorary evaporated with a 40° C. bath under vacuum overnight to remove residual water. This afforded 116 g of pink solid which was suspended in acetone (600 mL) and heated to reflux for 1 hour, then removed from the heat, cooled to room temperature, and stirred for a further hour. The suspension was filtered and the filter cake was washed with acetone (˜500 mL) until the filtrate was colorless. The filter cake was dried to afford desired product (108.7 g, 89% yield). 1H NMR (CDCl3, 400 MHz) 5=8.39 (s, 1 H) 8.24 (s, 1 H) 8.11 (s, 1 H) 7.82 (d, J=8.59 Hz, 2 H) 7.32 (d, J=8.20 Hz, 2 H) 3.93 (s, 3 H) 2.40 (s, 3 H); MS (ES+) 441.9 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].OS(O)(=O)=O.C([O-])(O)=O.[Na+].[CH3:30][CH2:31]O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][C:5]=1[C:6]([O:8][CH2:30][CH3:31])=[O:7])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Yield: 65 %

Procedure:
A solution of 34A (4.5 g, 17.4 mmol) in EtOH (120 mL) was treated with concentrated H2SO4 (4 mL) and heated to reflux for 24 hours. The mixture was cooled to room temperature and neutralized with 5% NaHCO3. The resulting solution was extracted with CH2Cl2, dried (MgSO4), filtered, and concentrated to afford 43A (2.6 g, 65%).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>C1COCC1.CCN(CC)CC>[OH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:2][C:3]#[N:4])[CH2:8][CH2:7]1
Reactant: N#CCBr
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCN1CCC(O)CC1
Temperature: 47.5 °C
Yield: 56858.5 %

Procedure:
BrCH2CN (28.55 g, 0.238 mmol) was added dropwise to a solution of 4-hydroxypiperidine (24.98 g, 0.216 mol) and Et3N (33.18 mL, 0.238 mmol) in dry THF (100 mL) under N2, maintaining the temperature between 45-50° C. After addition of BrCH2CN, the solution was refluxed for 30 min., before allowing the solution to cool down to room temperature. The title-compound was afforded as a straw-coloured oil (18.97 g, 63%) after purification by flash chromatography using ether/CH3OH (19:1) as eluent. dH (250 MHz; CDCl3); 1.65 (m, 2H, 1×CH2CH2CH and 1×CHCH2CH2), 1.75 (s, 1H, OH), 1.95 (m, 2H, 1×CH2CH2CH, 1×CHCH2CH2), 2.45 (m, 2H, 1×NCH2CH2 and 1×NCH2CH2), 2.78 (m, 2H, 1×NCH2CH2 and 1×NCH2CH2), 3.55 (s, 2H, NCH2CN) and 3.75 (m, 1H, CH2CHOH); δC (62.9 MHz; CDCl3); 33.96, 46.09, 49.73, 66.58 and 114.71 (CN); IR υmax/cm−1; 3375(broad), 2230, 1420, 1330, 1150 and 1060; FAB MS, m/z(M+H)+ 141.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)=[C:20]([F:25])[CH:19]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(oc3ccccc32)c1Nc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 0.11 mL (0.97 mmol) of 4-chloro-2-fluoroaniline in 6 mL of 2-ethoxyethanol is heated at reflux temperature for 4 days. A catalytic amount of pyridine hydrochloride is added and the reaction mixture is heated at reflux temperature overnight then cooled to room temperature. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo to provide 120 mg (40%) of a beige solid, mp 259–261° C.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[O:27][C:28](=[O:31])[CH2:29]I)[CH3:2].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].O>C(Cl)Cl>[CH2:32]([N:34]([CH2:29][C:28]([O:27][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)=[O:31])[CH2:35][CH3:36])[CH3:33]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CI
Reactant: CCNCC
Solvent: ClCCl
Solvent: O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CN(CC)CC
Temperature: 25 °C

Procedure:
2β-Ethoxy-3α-iodoacetoxy-5α-pregnane-11,20-dione (460 mg) was dissolved in methylene chloride (25 ml) and diethylamine (1 ml) added to the solution. The mixture was stirred at room temperature for one-half hour. The mixture was poured into water and the organic layer washed with water (100 ml.), dried over anhydrous sodium sulphate and evaporated to a red oil (410 mg.) which was purified by preparative T.L.C. using ethyl acetate/petrol (2/1) run twice. The main band (RF 0.4) gave title compound (230 mg) as a pale yellow oil [α]D + 100° (c = 0.9).
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([CH3:19])([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:20])[CH:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:19][C:11]([N:8]1[CH2:9][CH2:10][CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:7]1=[O:20])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC1CCN(C(C)(C)c2ccccc2)C(=O)C1c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(c1ccccc1)N1CCC=C(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
4.2 g (0.012 mol) of 4-acetoxy-1-(α,α-dimethylbenzyl)-3-phenyl-2-piperidone prepared by the method of Reference Example 20, was dissolved in 100 ml of toluene, and 2.7 g (0.018 mol) of DBU was added thereto. The mixture was refluxed under heating for 10 minutes. The reaction solution was cooled to room temperature and washed with water. Then, the solvent was distilled off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 3.0 g (yield: 75.0%) of the desired compound.
Reaction SMILES: C(O)CCC.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][C:17]1[CH:22]=[C:21]([C:23](CC)(C)C)[CH:20]=[C:19](C(CC)(C)C)[C:18]=1[OH:33])([O-])=[O:7].[N+](C1C=CC(C)=CC=1N=NC1C=CC=CC=1O)([O-])=O>C(O)CC>[OH:33][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[N:16]1[N+:6]([O-:7])=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:15]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: Cc1ccc([N+](=O)[O-])c(N=Nc2ccccc2O)c1
Solvent: CCCO
Solvent: CCCCO
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Yield: 87.9 %

Procedure:
The same procedure as in Example 1 was repeated, except that n-butanol 80 g was replaced by n-propanol 80 g, and that 2-nitro-2'-hydroxy-3',5'-di-t-amylazobenzene 25.5 g was replaced by 2-nitro-2'-hydroxy-5-methylazobenzene 17.1 g, thus producing 14.1 g of 2-(2-hydroxy-5-methylphenyl)benzotriazole-N-oxide having a melting point of 138° to 140° C. at the yield of 88%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]=[C:8]([C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO.C(O)C>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1nc2ccccc2s1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1nc2ccccc2s1

Procedure:
To a stirred suspension of 10% palladium on carbon (50 mg) in methanol (5 mL) was added a solution of 3-(benzothiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acidtert-butyl ester 29-7c (190 mg) in ethanol (5 mL) and the mixture was subjected to an atmosphere of hydrogen for 48 hours. The reaction mixture was filtered through Celite and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with 4:1 hexanes/acetone to give 29-8c as a colorless oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:34]([C:31]4[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:36])[F:37])=[CH:29][CH:30]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 4-trifluoromethoxy-phenylhydrazine according to the method described for example 43. MS: M=477.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:6]([CH2:12]Cl)=[N:7]2.[I:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2[NH2:33])[NH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:33][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:26]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:25]=[C:24]([I:23])[C:32]=12
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a stirred mixture of 5-bromo-3-(2-chlorobenzyl)-2-(chloromethyl)quinazolin-4(3H)-one, (2), (13.6 g, 30.7 mmol) and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3) (8.09 g, 30.7 mmol) in DMF (300 mL was added potassium carbonate (6.36 g, 46.0 mmol) and the reaction maintained at RT in the dark for 24 hr. The mixture was poured onto water (4.0 L) and the resulting suspension was stirred at RT for 1 hr. The precipitate was isolated by filtration and dried in vacuo to afford the title compound, (4), as a colourless solid (18.0 g, 94%); Rt 2.17 min; m/z 622/624 [M+H]+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.[NH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][N:29]([CH3:35])[CH2:30]2>CN(C=O)C>[CH3:35][N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[CH:34][C:25]=2[NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([CH3:13])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:30]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(C)c(Cl)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2
Temperature: 25 °C
Yield: 43.2 %

Procedure:
5-Chloro-2-methoxy-4-methylbenzoic acid (0.202 g, 1 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (0.200 g, 1 mmol) and 1-hydroxy-benzotriazole (0.155 g, 25 mmol) were dissolved in dry DMF (10 ml) and stirred at room temperature under argon for 25 mins before 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.163 g, 1 mmol) was added. The mixture was then stirred for 24 under argon at room temperature. The DMF was removed in vacuo and the residue suspended in ethyl acethate and washed with water. The insoluble white precipithate was filtered off, washed with water then dried to afford the title compound (149 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][NH:5][C:4](=[O:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].O>CS(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[CH:6]=[C:7]([CH3:8])[C:2](=[O:1])[NH:3][C:4]1=[O:9]
Reactant: ClCCCCBr
Reactant: Cc1c[nH]c(=O)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
10.1 g (80.0 mmol) of 4-hydroxy-5-methylpyrimidin-2(1H)-one (thymine) in 300 ml of dimethyl sulfoxide (DMSO) and 11.1 g (80.0 mmol) of K2CO3 were stirred at room temperature for 1 hour. Then 13.7 g (80.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to the mixture, and the reaction mixture was then stirred at room temperature for 5 hours. Water was added to the reaction mixture, and it was then extracted with ethyl acetate. The aqueous phase was then neutralized and extracted with methylene chloride. Drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo resulted in 7.1 g of the title compound
Reaction SMILES: Cl[C:2]1[C:3]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([NH:8]C(=O)C)[N:7]=1.[CH2:23]([Mg]Br)[CH3:24]>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:23]([C:2]1[C:3]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1)[CH3:24]
Reactant: CC[Mg]Br
Reactant: CC(=O)Nc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2 %

Procedure:
A mixture of N-[4-chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide (63 mg, 0.2 mmol; the synthesis of which has been disclosed in WO 2006/135993) and iron tris(acetylacetonate) (10 mg, 0.028 mmol) in THF (2 ml) and NMP (1 ml) was added ethylmagnesium bromide (0.6 ml, 0.6 mmol; 1.0 M solution in THF). After stirring at room temperature for 10 minutes, the solution was diluted with THF and quenched by adding a solution of 0.2 N HCl. The mixture was extracted with ethyl acetate, then dried over Na2SO4 and concentrated. The residue was dissolved in methanol (1 ml) and then sodium methoxide (0.2 ml; 0.5 N solution in methanol) was added. The mixture was heated to 120° C. for 10 minutes under microwave irradiation. Solvents were concentrated in vacuo and the residue was purified by HPLC using a C18 column with a gradient of H2O and 0.1% TFA-acetonitrile, to provide the pure title compound as a white solid (1 mg, yield: 2%) which was characterised by its mass spectrum as follows: MS (m/z) 269.0 [M+H]+; HPLC Rt=4.14 minutes (Method A).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH:6]1([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[N:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=O)=[O:16])[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1>>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:20]([C:19]1[CH:23]=[CH:24][N:25]=[CH:26][C:18]=1[NH:17][C:15]([C:13]1[C:12]([NH:27][C:28]2[CH:33]=[N:32][CH:31]=[N:30][CH:29]=2)=[CH:11][CH:10]=[C:9]([CH:6]2[CH2:7][CH2:8]2)[N:14]=1)=[O:16])=[O:22]
Reactant: CNCCO
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CN(CCO)C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 32 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-methylamino-ethanol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (32%) as amorphous yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:15][CH2:16]OCC>CCO>[CH2:15]([O:9][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3][CH2:4]1)=[O:10])[CH3:16]
Reactant: NC1CCC(C(=O)O)CC1
Reactant: CCOCC
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-amino-cyclohexanecarboxylic acid (G) (5 g, 35 mmol) in EtOH (175 mL) at 0° C. was added SOCl2 (12.6 mL, 174 mmol) dropwise via a syringe. The reaction mixture was warmed to room temperature and stirred for 16 h. After concentration of the reaction mixture, ether was added and the suspension was filtered to give 4-amino-cyclohexanecarboxylic acid ethyl ester (H) (mixture of cis/trans) as a white solid (4.8 g): 1H NMR (300 MHz, CDCl3) δ8.35 (br s, 3 H), 4.18 (m, 2 H), 3.36-3.15 (m, 1 H), 2.54 (m, 1 H), 2.30-1.45 (series of m, 8 H), 1.13 (t, 3 H); mass spectrum m/z 172 [(M+H)+; calcd for C9H18NO2: 172].
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[NH:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:24]I>>[CH3:24][N:13]1[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[CH:2]=[O:1])=[N:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:14]1
Reactant: Cc1ccc(-c2nc(-c3cccc(C4OCCO4)c3)n[nH]2)cc1
Reactant: CI
Product: Cc1ccc(-c2nc(-c3cccc(C=O)c3)n(C)n2)cc1

Procedure:
Using 3-(3-[1,3]dioxolan-2-yl-phenyl)-5-p-tolyl-1H-[1,2,4]triazole (mixture of tautomers) and methyl iodide the title compound was obtained as white solid (41% yield), MS: m/e=277.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:17]=[C:18]([C:25](O)=[O:26])[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:18]2[N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]3=[N:16][CH:17]=2)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1cnc2ccccn12
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cnc3ccccn23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with imidazo[1,2-a]pyridine-3-carboxylic acid. LC-MS (acidic): tR=0.74 min; [M+H]+=357.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](Cl)=[O:33].C(N(CC)CC)C>ClCCl>[CH:23]1[CH:22]=[CH:21][N:13]2[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])=[N:7][CH:6]=3)=[O:9])[CH2:11][C:12]=12
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.0 mmol of 10,11-dihydro-10-(6-amino-3-pyridinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 2.1 mmol of 2-methylbenzeneacetyl chloride and 5 mmol of triethylamine in 10 ml of dichloromethane is stirred under argon at room temperature for 16 hours. The solvent is removed under vacuum and the residue partitioned between 50 ml of ethyl acetate and 25 ml of water. The organic layer is separated, washed with H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.