Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C@@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14]Cl)[CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([CH2:14][CH2:13][C@@H:12]([O:11][C:4]1[CH:3]=[C:2]([Br:1])[C:9]([F:10])=[CH:8][C:5]=1[C:6]#[N:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+:23]=[N-:24]
Reactant: N#Cc1cc(F)c(Br)cc1O[C@H](CCCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: N#Cc1cc(F)c(Br)cc1O[C@H](CCN=[N+]=[N-])c1ccccc1

Procedure:
This was prepared by the method of Example 68(b) using 4-bromo-2-[[(1R)-3-chloro-1-phenylpropyl]oxy]-5-fluorobenzonitrile and sodium azide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([Sn]([N:26]=[N+:27]=[N-:28])(CCCC)CCCC)CCC.[N-]=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]1[N:26]=[N:27][NH:28][N:5]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [N-]=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(-c2nn[nH]n2)c1
Yield: 127.7 %

Procedure:
137 mg (0.750 mmol, 1 eq.) of 2-chloro-5-nitrobenzonitrile are dissolved in 8 mL of toluene, and 411 μl (1.5 mmol, 2 eq.) of tributyl tin azide are added to the reaction mixture. Then the mixture is heated under reflux of the toluene for one night. As the reaction is incomplete, 205 μl (0.75 mmol, 1 eq.) of azide are again added and the mixture is stirred under reflux for a further 5 hours. The mixture is then concentrated and 10 mL of HCl 2 N in Et2O are added, the precipitate formed is filtered and washed with pentane and diethyl ether. 216 mg of product 10 are obtained (yield=64%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][S:12][CH2:13][CH3:14].[NH3:15]>O>[CH2:13]([S:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:15])[CH3:14]
Reactant: N
Reactant: CCSCn1cnc2c(Cl)ncnc21
Solvent: O
Product: CCSCn1cnc2c(N)ncnc21
Temperature: 60 °C

Procedure:
6-Chloro-9-ethylthiomethylpurine (1.5 g) and liquid ammonia (20 ml) were placed in a bomb and heated at 60° C. overnight. Evaporation of the ammonia gave a residue which was treated with cold water, filtered, and washed with cold water. This yielded 9-ethylthiomethyladenine (1.17 g) as a white solid, m.p. 140°-142° C. Recrystallization from ethanol gave white plates, m.p. 142°-143° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C1C=CC=CN=1)C.N1C=CN=C1.[Si:51](Cl)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>N1C=CC=CC=1>[Si:51]([O:4][C@@H:3]1[C@@H:5]([CH2:6][OH:7])[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: CN(C)c1ccccn1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of 2'-deoxyuridine (5.00 g, 22 mmol) in pyridine (20 ml) was added triphenylmethyl chloride (6.72 g, 24 mmol) and dimethylaminopyridine (0.20 g, 1.6 mmol). The mixture was allowed to stir at 80° C. for 30 min. The pyridine was removed under reduced pressure and the residue dissolved in DMF (30 ml). Imidazole (3.59 g, 53 mmol) and t-butyldimethylsilyl chloride (3.92 g, 26 mmol) were added, and the mixture was allowed to stir overnight at room temperature. The DMF was removed under reduced pressure, and the residue was dissolved in 80% aqueous acetic acid (20 ml). The mixture was allowed to reflux for 30 min, cooled, and neutralized with NaOH. The mixture was lyophilized, and the residue was purified by chromatography (1:1 EtOAc: hexanes) to give 22 as a white solid (3.13 g, 9.14 mmol, 41.51% yield): mp 140° C. (softens), 160°-170° C. (melts); Rf 0.65 (1:9 MeOH:CH2Cl2); 1H NMR (CDCl3) 7.62(d, 1H, J=6.87 Hz), 6.16(t, 1H, J=6.61), 5.73(d, 1H, J=5.70 Hz), 4.49(m, 1H), 3.93(m, 2H), 3.76(m, 1H), 2.30(m, 1H), 2.19(m, 1H), 0.89(s, 9H), 0.09(s, 6H)ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:28][CH2:29]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:32][CH2:29][CH2:28][CH:9]1[CH2:10][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCO
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In methylene chloride (50 ml) was dissolved 1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-hydroxylethyl)piperazine (1.00 g), followed by the addition of carbon tetrabromide (1.46 g) and triphenylphosphine (1.15 g). The resulting mixture was stirred at room temperature for 30 minutes. After the addition of a saturated aqueous solution of sodium sulfite, the organic layer was collected from the mixture. The organic layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column [hexane:ethyl acetate=10:1 to 6:1], whereby the title compound (990 mg) was obtained as a colorless foam.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])=[CH:4][C:3]=2[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([CH3:15])([CH3:14])[CH2:11][OH:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C(=O)O)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc2c(c1)OCO2

Procedure:
In tetrahydrofuran, 2-(3,4-methylenedioxyphenyl)-2-methylpropionic acid was reduced with lithium aluminum hydride to give 2-(3,4-methylenedioxyphenyl)-2-methylpropyl alcohol.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=4)=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1.C([NH:35][S:36](Cl)(=[O:38])=[O:37])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH2:23][CH2:24][N:25]([S:36]([NH2:35])(=[O:38])=[O:37])[CH2:26][CH:27]=4)=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(Nc2ncc(-c3ccc(C4=CCNCC4)cc3)o2)c1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1

Procedure:
The title compound is prepared from (3-chlorophenyl)-{5-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-oxazol-2-yl}-amine bis HCl salt in analogous fashion using N-Boc chlorosulfonamide followed by TFA-mediated deprotection: 1H NMR (400 MHz, DMSO-d6) δ 2.55 (br. s., 2H) 3.15 (t, J=5.56 Hz, 2H) 3.65 (d, J=2.78 Hz, 2H) 6.22 (t, J=3.28 Hz, 1H) 6.92 (dd, J=7.83, 1.52 Hz, 1H) 7.26 (t, J=8.08 Hz, 1H) 7.39-7.53 (m, 7H) 7.79 (t, J=2.02 Hz, 1H); (M+H)+431.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:19][C:8]=2[S:9][C:10]=1[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5])C.[OH-].[K+]>C(O)C.O.Cl>[C:15]([O:14][C:12]([NH:11][C:10]1[S:9][C:8]2[CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:21]=[CH:22][C:7]=2[C:6]=1[C:4]([OH:5])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1c(NC(=O)OC(C)(C)C)sc2cc(-c3ccc(F)cc3)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1sc2cc(-c3ccc(F)cc3)ccc2c1C(=O)O
Yield: 82.9 %

Procedure:
A solution of 1f (80 mg, 0.193 mmol) in ethanol/water (1:1, 10 mL) was mixed with KOH (21.6 mg, 0.39 mmol). The resultant mixture was heated at 60° C. for 1 h, diluted with HCl (30 mL, 1N), and extracted with ethyl acetate (30 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated to afford the title compound (62 mg, 84%) as a white solid: MS (ES) m/z 388 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5[N:26]=[CH:27][N:28](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:29]=5)[CH:20]=4)=[O:17])=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH:29]=[C:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16]([C:13]3[CH:14]=[CH:15][C:10]4[N:9]=[C:8]5[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]5[C:11]=4[CH:12]=3)=[O:17])[CH:24]=[CH:23][CH:22]=2)[N:26]=[CH:27]1
Reactant: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2nc3n(c2c1)CCCNC3=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2c[nH]cn2)c1)c1ccc2nc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 1-oxo-N-[3-(1-trityl-1H-imidazol-4-yl)phenyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxamide (53 mg, 0.08 mmol) in CH2Cl2 (3 mL) is added TFA (0.5 mL) and the solution is stirred for 2 h at room temperature. The solvent is evaporated and the residue treated with 0.1M aqueous NaOH solution. A brown solid is formed which is collected by filtration, washed with CH2Cl2, and dried to afford the title compound (26 mg, 80%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.Br[C:26]1[N:34]2[C:29]([CH:30]=[N:31][C:32]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)=[CH:38][CH:37]=3)=[N:33]2)=[CH:28][CH:27]=1.[CH3:49][NH:50][S:51]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56](B(O)O)[CH:55]=1)(=[O:53])=[O:52].C(=O)([O-])[O-].[Na+].[Na+].O.C(O)C.[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:49][NH:50][S:51]([C:54]1[CH:55]=[CH:56][CH:57]=[C:58]([C:26]2[N:34]3[C:29]([CH:30]=[N:31][C:32]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([N:42]5[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]5)=[CH:40][CH:41]=4)=[N:33]3)=[CH:28][CH:27]=2)[CH:59]=1)(=[O:52])=[O:53]
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.7 %

Procedure:
Palladium Acetate (0.017 g, 0.000077 mol) and Triphenylphosphine (0.025 g, 0.000097 mol) were dissolved in Tetrahydrofuran (1.2 mL, 0.014 mol) and the mixture was allowed to stir at room temperature for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.125 g, 0.000323 mol) was then added and the reaction was again allowed to stir for 10 minutes. N-methyl-3-boronobenzenesulfonamide (0.166 g, 0.000775 mol) was added followed by 0.9 M of Sodium carbonate in water (0.9 mL, 0.0008 mol) and Ethanol (1.2 mL, 0.020 mol). The reaction mixture was then heated at 80° C. and was allowed to stir overnight. The reaction mixture was poured over saturated sodium chloride, and organics were extracted with ethyl acetate. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Gilson prep HPLC to afford 38.12 mg of N-Methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide as a lyophilized powder. (M+H)=478.1. 1H NMR (400 MHz, DMSO, d6) δ 9.74 (s, 1H), 9.40 (s, 1H), 9.02 (s, 1H), 8.53 (s, 1H), 8.40 (m, 1H), 7.76 (m, 2H), 7.68 (m, 2H), 7.55 (m, 1H), 7.19 (d, 1H, J=4.28 Hz), 7.04 (m, 1H), 6.98 (d, 1H, J=4.32 Hz), 3.72 (m, 2H), 3.53 (m, 2H), 3.20 (m, 2H), 2.94 (m, 2H), 2.91 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:11]([CH3:24])[C:10]=2[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[O:26])=[CH:5][N:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[N:11]([CH3:24])[C:10]=2[C:25]([N:27]2[CH2:28][CH2:29][CH:30]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:31][CH2:32]2)=[O:26])=[CH:5][N:4]=1
Reactant: COc1ncc(-c2nc(-c3ccc(C(F)(F)F)cc3)n(C)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2cnc(O)nc2)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
A solution of 0.25 g (0.49 mmol) of [5-(2-methoxy-pyrimidin-5-yl)-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 114) in 10 ml of MeCl2 was cooled down to 0° C.; then, 0.97 ml (1.0 mMol) of a boron tribromide solution (1.0 molar in MeCl2) were added and the reaction mixture was warmed up to RT. After 3 hours, it was poured into crashed ice, neutralized with an aqueous sodium hydrogen carbonate solution, then extracted twice with MeCl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 0.089 g (37%) of the title compound as yellow solid. MS: 501.2 (MH+).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 117.3 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (680 mg, 1.24 mmol) and 10% palladium on activated carbon (204 mg) in methanol (300 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb and kept for 5 h. The mixture was cooled to 25° C., the solids were filtered off, washed with ethyl acetate and the filtrate concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (600 mg, 87%) which was used without further purification.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]([NH2:11])([CH3:10])[CH3:9].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:34][C:35]1[CH:36]=[C:37]([CH:45]=[C:46]([Cl:48])[CH:47]=1)[O:38][CH:39]([CH2:43][CH3:44])[C:40](O)=[O:41]>CN(C)C=O.O.C(N(CC)CC)C>[Cl:34][C:35]1[CH:36]=[C:37]([CH:45]=[C:46]([Cl:48])[CH:47]=1)[O:38][CH:39]([CH2:43][CH3:44])[C:40]([NH:11][C:8]([CH3:10])([CH3:9])[C:7]#[C:6][CH2:5][CH2:4][CH2:3][Cl:2])=[O:41]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: CC(C)(N)C#CCCCCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
1-Chloro-6-methylhept-4-yn-6-yl amine hydrochloride (9.8 g) in N,N-dimethylformamide (250 ml) containing triethylamine (10.4 ml) was stirred at ambient temperature for 10 minutes. The suspension which had formed was treated sequentially with 1-hydroxybenzotriazole (7.59 g), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.56 g) then 2-(3,5-dichlorophenoxy)-butyric acid (13.07 g) in N,N-dimethylformamide (50 ml). The mixture was stirred at ambient temperature for 2 hours, stored for 18 hours then poured into water. The product was extracted with ethyl acetate (three times). The extracts were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate and water (three times) and dried over magnesium sulphate. They were then evaporated under reduced pressure to give the required product as a yellow gum (19.1 g) sufficiently pure for further derivatisation. A portion of the gum (0.33 g) was fractionated by chromatography (silica; hexane/diethyl ether, 4:1 by volume) to provide a pure sample of 2-(3,5-dichlorophenoxy)-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide as a colourless oil, 0.22 g, 1H NMR (CDCl3) δ: 1.00-1.04(3H, t); 1.58(6H, s); 1.90-2.00(4H, m); 2.36-2.40(2H, t); 3.62-3.66(2H, t); 4.36-4.40(1H, t); 6.26(1H, s); 6.84(2H, s); 7.02(1H, s).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[CH:22])[C:7]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[CH:22])[C:7]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])=[C:6]([CH:28]([CH3:29])[CH3:30])[N:5]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1-c1c(C=CCCC)c(C(C)C)nc(C(C)C)c1C(=O)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#Cc1ccccc1-c1c(C=CCCC)c(C(C)C)nc(C(C)C)c1CO

Procedure:
The title compound was prepared from the intermediate obtained in Step D by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.81 (t, J=7.4 Hz, 3 H), 1.0-1.40 (m, 15 H), 1.75 (m, 2 H), 2.98 (d, J=3.3 Hz, 1 H), 3.20-3.60 (m, 2 H), 4.20-4.50 (m, 2 H), 5.40 (m, 1 H), 6.0 (m, 1 H), 7.0-7.60 (m, 4 H). Rf=0.23 (10% ethyl acetate/n-hexane).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([CH3:15])[CH:5]=1)([O-])=O.O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([CH3:15])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-c1cnco1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Cc1cc(N)ccc1-c1cnco1

Procedure:
2Bromo-5-nitrotoluene (1.0 g, 4.54 mmol) and vinyltributyl tin (1.59 g, 4.99 mmol) were dissolved in toluene (25 mL) under argon. Palladium dibenzylidene acetone (4.15 g, 0.455 mmol) and triphenylphosphine (488 mg, 1.86 mmol) was added and the reaction refluxed overnight. The solvent was evaporated and the residue dissolved in 200 mL of methylene chloride and washed with 10% ammonium hydroxide, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography heptane-methylene chlolride 1:1) to yield 726 mg of 2-methyl-4-nitrostyrene. 2-methyl-4-nitrostyrene (700 mg, 4.5 mmol) was dissolved in methylene chloride (20 mL) and cooled to −78° C., and treated with ozone until a blue color remained, after 5 minutes the excess ozone was removed by passing a stream of oxygen through the solution. Dimethyl sulfide (1 mL) was added and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography to yield 580 mg of the 2-methyl-4-nitrobenzaldehyde. 2-Methyl-4-nitrobenzaldehyde (570 mg, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) were suspended in methanol. Tosylmethylisocyanide (674 mg, 3.45 mmol) was added and the reaction mixture refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 710 mg (94%) of 5-(4-nitro-2-methylphenyl)oxazole. 5-(4-Nitro-2-methylphenyl)oxazole was dissolved in methanol (100 mL) and 10% palladium on carbon 200 mg was wetted with water and added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and 560 mg of 5-(4-amino-2-methylphenyl)oxazole was isolated in 92% purity by HPLC method A. Mass spectrum M+H+=175.1, 1H 400 MHz NMR (CDCl3): δ7.88 (s, 1H), 7.45 (m, 1H), 7.08 (s, 1H), 6.60 m(m, 2H), 2.38 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH2:17][CH3:18])=O>N1C=CC=CC=1>[CH2:16]([O:15][C:13]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH2:17][CH3:18]
Reactant: CCCOC(=O)Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: c1ccncc1
Product: CCCOc1nc2ccc(C)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with propyl chloroformate (3.0 ml, 26 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 h, after which time the pyridine was removed in vacuo. The residue was washed with water (25 ml) and dried in vacuo to afford the desired product as an off-white solid (0.96 g, 66%); δH (400 MHz, DMSO-d6) 1.03 (3H, t, J 7, CH2CH3), 1.82 (2H, tq, J, J′ 7, CH2CH3), 2.46 (3H, s, CH3), 4.42 (2H, t, J 7, OCH2), 7.40 (1H, d, J 8, Ph), 7.71 (1H, d, J 8, Ph), 7.89 (1H, s, Ph); m/z (ES+) 219 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:34][C:35](=O)[CH2:36][CH2:37][N:38]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]1=[O:48])[C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:54]>C(O)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[CH:34]=[C:35]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])[N:54]=[C:25]1[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)N(CC(=O)CCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc(CCN3C(=O)c4ccccc4C3=O)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 51.4 %

Procedure:
A solution of N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-N-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-oxo-butyl]-4-methyl-benzamide (641 mg, 0.948 mmol) and ammonium acetate (3.65 g, 47.4 mmol) in acetic acid (30 mL) was refluxed for 6.0 h using a Dean-Stark trap and condenser. The reaction was concentrated in vacuo and the residue was triturated with water, dried in a Buchner funnel, and recrystallized from ethanol to provide the title compound as a white solid (320 mg, 51%). MS(ES+) m/e 656 [M+H]+.