Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:21][O:22][C@H:23]1[O:28][C@H:27]([CH2:29][O:30][S:31]([O-:34])(=[O:33])=[O:32])[C@@H:26]([O:35][C@@H:36]2[O:41][C@@H:40]([C:42]([OH:44])=[O:43])[C@@H:39]([O:45][C@H:46]3[O:51][C@H:50]([CH2:52][O:53][S:54]([O-:57])(=[O:56])=[O:55])[C@@H:49]([O:58][C@@H:59]4[O:64][C@H:63]([C:65]([OH:67])=[O:66])[C@@H:62]([O:68][C@H:69]5[O:74][C@H:73]([CH2:75][O:76][S:77]([O-:80])(=[O:79])=[O:78])[C@@H:72]([OH:81])[C@H:71]([OH:82])[C@H:70]5[NH:83][S:84]([O-:87])(=[O:86])=[O:85])[C@H:61]([OH:88])[C@H:60]4[OH:89])[C@H:48]([O:90][S:91]([O-:94])(=[O:93])=[O:92])[C@H:47]3[NH:95][S:96]([O-:99])(=[O:98])=[O:97])[C@H:38]([OH:100])[C@H:37]2[O:101][S:102]([O-:105])(=[O:104])=[O:103])[C@H:25]([OH:106])[C@H:24]1[NH:107][S:108]([O-:111])(=[O:110])=[O:109].[Na+:112].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>O>[CH2:10]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8])[CH2:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:18]([OH:20])=[O:19].[CH3:21][O:22][C@H:23]1[O:28][C@H:27]([CH2:29][O:30][S:31]([O-:34])(=[O:32])=[O:33])[C@@H:26]([O:35][C@@H:36]2[O:41][C@@H:40]([C:42]([OH:44])=[O:43])[C@@H:39]([O:45][C@H:46]3[O:51][C@H:50]([CH2:52][O:53][S:54]([O-:57])(=[O:56])=[O:55])[C@@H:49]([O:58][C@@H:59]4[O:64][C@H:63]([C:65]([OH:67])=[O:66])[C@@H:62]([O:68][C@H:69]5[O:74][C@H:73]([CH2:75][O:76][S:77]([O-:80])(=[O:78])=[O:79])[C@@H:72]([OH:81])[C@H:71]([OH:82])[C@H:70]5[NH:83][S:84]([O-:87])(=[O:85])=[O:86])[C@H:61]([OH:88])[C@H:60]4[OH:89])[C@H:48]([O:90][S:91]([O-:94])(=[O:93])=[O:92])[C@H:47]3[NH:95][S:96]([O-:99])(=[O:98])=[O:97])[C@H:38]([OH:100])[C@H:37]2[O:101][S:102]([O-:105])(=[O:104])=[O:103])[C@H:25]([OH:106])[C@H:24]1[NH:107][S:108]([O-:111])(=[O:110])=[O:109].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112]
Reactant: O=C(O)c1cccc(/C=C/c2ccccc2C(=O)O)c1
Agent: CO[C@H]1O[C@H](COS(=O)(=O)[O-])[C@@H](O[C@@H]2O[C@@H](C(=O)O)[C@@H](O[C@H]3O[C@H](COS(=O)(=O)[O-])[C@@H](O[C@@H]4O[C@H](C(=O)O)[C@@H](O[C@H]5O[C@H](COS(=O)(=O)[O-])[C@@H](O)[C@H](O)[C@H]5NS(=O)(=O)[O-])[C@H](O)[C@H]4O)[C@H](OS(=O)(=O)[O-])[C@H]3NS(=O)(=O)[O-])[C@H](O)[C@H]2OS(=O)(=O)[O-])[C@H](O)[C@H]1NS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(CCc2ccccc2C(=O)O)c1

Procedure:
Hydrogenation of (E)-stilbene-2,3'-dicarboxylic acid bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamide) decasodium salt (see Example 75) as described under Example 10 gave 2,3'-ethylenedibenzoic acid bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamide) decasodium salt, [α]D20 -10.0° (c 0.5; water), MS: m/z 1617.2 (reconstructed M).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[C:26](=[N:34]O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:17][C:16]([C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]4)=[CH:15][CH:14]=3)=[N:34][C:26]=2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][CH:20]=1
Reactant: NCc1ccc(N2CCN(CCO)CC2)cc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(N3CCN(CCO)CC3)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
4-[4-(2-Hydroxyethyl)piperazin-1-yl]phenylmethylamine and tert-butyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate are dissolved in pyridine, and the solution is treated in the same manner as in Starting Material Synthetic Example 170 to give the objective tert-butyl 5-(4-chlorophenyl)-2-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}imidazole-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[OH:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:26]([CH:27]3[CH2:32][CH2:31][CH:30]([CH2:33][OH:34])[CH2:29][CH2:28]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCC(CO)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCC(CO)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(4-hydroxymethyl-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 4-hydroxymethyl-1-cyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white solid. MS m/e: 489.2 [M+H]+.
Reaction SMILES: I.CN([CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)C.CI.C[O-].[Na+].[N+:20]([CH:23]([CH3:25])[CH3:24])([O-:22])=[O:21]>CO.C(OCC)(=O)C.[NH4+].[Cl-]>[CH3:24][C:23]([N+:20]([O-:22])=[O:21])([CH3:25])[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2ncccc12
Agent: C[O-]
Agent: I
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CI
Product: CC(C)(Cc1c[nH]c2ncccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A 0° C. solution of 3-dimethylaminomethyl-1H-7-azaindole hydroiodide (10 g, 33 mmol) in 46 ml of methanol and 46 ml of 2-nitropropane is treated with methyl iodide (2.15 ml, 35 mmol) and solid sodium methoxide (3.65 g, 68 mmol) sequentially. The resulting mixture is allowed to warm to ambient temperature, and, after stirring overnight, the reaction mixture is diluted with ethyl acetate (100 ml) and saturated aqueous NH4Cl solution (100 ml). The aqueous layer is extracted with ethyl acetate (2×100 ml), and the combined organic layers are dried over Na2SO4 and concentrated in vacuo to give 3-(2-methyl-2-nitropropyl)-1H-7-azaindole in 92% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:5][C:6]=1[C:7]#[N:8].[H-].[Na+].[NH2:16]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:16][N:5]1[C:6]([C:7]#[N:8])=[C:2]([Br:1])[CH:3]=[C:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc(Br)c(C#N)[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)c(C#N)n1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 4-bromo-5-cyano-1H-pyrrole-2-carboxylate (2.70 g, 11.1 mmol) in DMF (75 mL) was added 95% sodium hydride powder (323 mg, 12.8 mmol). The mixture was stirred (rt) for 20 min, then (aminooxy)(diphenyl)phosphine oxide (3.89 g, 16.7 mmol) was added in one portion. After 15 min, the reaction mixture became thick and additional DMF (25 mL) was added. The reaction was heated (50° C.) for 3 h and was allowed to cool to rt and stir for 17 h. The reaction was poured into saturated aqueous NaHCO3 solution (200 mL) and was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (2×100 mL), dried (Na2SO4) and were concentrated to dryness to afford 2.8 g (100%) of the desired product, which contained minor impurities. 1H NMR (300 MHz, DMSO-d6) δ 6.95 (s, 1 H), 6.57 (s, 2 H), 4.28 (q, 2 H), 1.29 (t, 3 H).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C=CC1C=CC=CC=1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1>[CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: O=C(O)C=Cc1ccccc1
Agent: [BH4-]
Solvent: C1CCOC1
Product: OCC=Cc1ccccc1

Procedure:
Scheme 5 illustrates a method for the synthesis of title compounds of general formula I wherein the R1 substituent is an carboxylic ester or similar functional group that can in turn be prepared from an ester. In this synthetic method, a cinnamaldehyde of general formula 22 is used as the starting material. If the cinnamaldehyde derivative of general formula 22 with the desired substitution pattern is not readily available, it may be prepared in two step from the cinnamic acid of general formula 20 as shown. In this case the cinnamic acid of general formula 20 is converted to a mixed anhydride with a reagent such as ethyl chloroformate in a solvent like THF. The intermediate mixed anhydride is then reduced with sodium borohydride which affords a cinnamyl alcohol of general formula 21. The cinnamyl alcohol of general formula 21 is then oxidized to the cinnamaldehyde of general formula 22 using one of the methods for the oxidation of alcohols known in organic synthesis. For example reaction of the cinnamyl alcohol of general formula 21 with DMSO and oxalyl chloride using the Swern modification of the Moffatt reaction affords the cinnamaldehyde 22. The aldehyde 22 is condensed with methyl azidoacetate under basic conditions to afford the azidodiene 23. Reaction of the azide 23 with triphenylphosphine affords the intermediate 2-aza-1λ5-phosphahexa-1,3,5-triene 24 which condenses with an benzaldehyde of general formula 25 to yield the methyl 5,6-diarylpyridine-2-carboxylate 26 after endocyclic ring closure and air oxidation of an intermediate dihydropyridine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:25])=[CH:11][N:10]=1)(C)(C)C.[ClH:40]>CCOC(C)=O>[ClH:40].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:25])=[CH:11][N:10]=1
Reactant: COc1cc2c(CC(=O)N3CCC(Cc4ccccc4)CC3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(CC(=O)N3CCC(Cc4ccccc4)CC3)cnc(CN)c2cc1OC
Yield: 100 %

Procedure:
As described in Example 1, 94 mg of {4-[2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 114 mg (>100%) of 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-1-(4-benzyl-piperidin-1-yl)-ethanone hydrochloride. MS: APCI (M+H) calc'd for C26H31N3O3+H 434.5; found 434.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[C:12]([N+:24]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe]>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:27]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1

Procedure:
The product from Example 26b was reduced with Fe and NH4Cl following the procedure form Example 10E to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][OH:6].N1C=CN=C1.[Si:21](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5][O:6][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
(R)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (2.2 mg, 10 mmol) was dissolved in THF (20 ml). Imidazole (818 mg, 12 mmol) and TBDPS chloride (2.9 ml, 11 mmol) were added. The mixture was stirred at rt overnight. The mixture was then partitioned between CH2Cl2 and water (30 ml/30 ml). The organic layer was concentrated and the residue was purified by column chromatography (6/1, Hexanes/EtOAc) to give (R)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionic acid methyl ester (3.3 g, 72%).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]O)[CH2:31][CH2:30]1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([O:17][CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:13][CH:12]=3)[N:19]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(O)cc12
Reactant: CN1CCN(CCO)CC1
Product: CN1CCN(CCOc2ccc3oc(-c4cc5ccccc5cn4)cc(=NO)c3c2)CC1

Procedure:
2-isoquinolin-3-yl-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-chromen-4-one oxime was prepared in 49% overall yield using the method described in examples 44 and 44A, starting from 6-hydroxy-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 41A) and 2-(4-methyl-piperazin-1-yl)-ethanol. The title compound was isolated as a yellow solid and as a 90/10 mixture of Z/E oxime isomers.
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[CH3:24].[Si]([O:32][CH2:33][CH2:34][C:35]#[C:36][B-](F)(F)F)(C(C)(C)C)(C)C.[K+].O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][C:3]1[N:4]2[C:10]([CH:9]([O:12][CH:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5]2)=[N:11][C:2]=1[C:36]#[C:35][CH2:34][CH2:33][OH:32]
Reactant: Cc1c(I)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCC#C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C#CCCO)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-iodo-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 133) (50 mg, 0.114 mmole) in THF (1 mL) are added potassium 4-tert-butyldimethylsilyloxybut-1-ynyltrifluoroborate (50 mg, 0.171 mmole), PdCl2(dppf)2 (8 mg, 0.011 mmole), water and Cs2CO3 (120 mg, 0.342 mmole). The flask is evacuated and filled with argon. The reaction mixture is heated at 80° C. for 24 hours. AcOEt and water are added, and the organic phase is washed with water, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (98:2) to (90:10) then (CH2Cl2:MeOH:NH4OH) (9:1:0.1). The residue is dissolved in nBu4NF 1M in THF (0.5 mL) and the reaction mixture is stirred overnight at room temperature. Water is added and the aqueous phase is extracted with AcOEt. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.1) to (96.5:3.5:0.35) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-but-3-yn-1-ol.
Reaction SMILES: Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:65]=[C:64]([N+:66]([O-])=O)[CH:63]=[CH:62][C:45]=1[O:46][C:47]1[C:52]2=[CH:53][C:54]([C:56]3[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1>>[F:43][C:44]1[CH:65]=[C:64]([NH2:66])[CH:63]=[CH:62][C:45]=1[O:46][C:47]1[C:52]2=[CH:53][C:54]([C:56]3[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3cc(-c4cccnc4)cc23)c(F)c1
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Nc1ccc(Oc2ncnn3cc(-c4cccnc4)cc23)c(F)c1
Yield: 46.7 %

Procedure:
Following a procedure similar to that for the synthesis of Compound C of Example 36, 4-(2-fluoro-4-nitrophenoxy)-6-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazine (35 mg, 0.10 mmol) was converted to the title compound (15 mg, 46%). MS(ESI+) m/z 322.3 (M+H)+.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]([NH:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:25]1([CH2:28][N:20]([CH2:21][CH2:22][CH3:23])[C:16]2[C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:2]4[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=4[CH3:24])=[N:11][C:12]=3[CH:19]=[CH:18][CH:17]=2)[CH2:27][CH2:26]1
Reactant: O=CC1CC1
Reactant: CCCNc1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CC1CC1)c1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To 0.041 g (0.13 mmol) of N2-mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine in 2 mL of methanol was added 95 μL (1.3 mmol) of cyclopropane carboxaldehyde, 200 μL of glacial acetic acid and 0.032 g (0.51 mmol) of sodium cyanoborohydride. The mixture was stirred at room temperature for 24 h. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The crude solid was partitioned between saturated sodium bicarbonate and dichloromethane, the organic layer was separated, dried over sodium sulfate, filtered, concentrated and purified by reverse-phase HPLC to give 0.026 g (42%) of the title compound as a colorless sticky solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](C)=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1.B(Br)(Br)Br.C1CCCCC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:12])[CH3:13])[N:8]=[C:7]2[C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nn(C(C)C)c3c(F)ccc(C)c23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)n1nc(-c2ccc(O)cc2)c2cccc(F)c21
Yield: 75.6 %

Procedure:
Prepared according to Method D step C from 7-fluoro-1-isopropyl-3-(4-methoxyphenyl)-methyl-1H-indazole (0.065 g, 0.23 mmol), boron tribromide (0.10 mL, 1.05 mmol) and 0.3 mL of cyclohexene to give the product (0.047 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15]O.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CO
Reactant: Cc1c(C(=O)O)ccc(Cl)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1C
Temperature: 75 °C

Procedure:
A round bottom flask was charged with 4-chloro-2-methyl-3-nitrobenzoic acid (11.00 g, 0.05102 mol) and methanol (110 mL, 2.7 mol) and thionyl chloride (4.5 mL, 0.061 mol) was added at 0° C. and the reaction heated at 75° C. for 3 hours. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (300 mL) and washed with aqueous sodium bicarbonate, water and brine. The organic extracts were dried over sodium sulfate and the solvent removed to recover the esters. MS m/z=230.3 (M+H).
Reaction SMILES: [NH2:1][C:2]([C:15]1[C:23]([O:24][CH:25]([F:27])[F:26])=[CH:22][C:21]([CH3:28])=[C:20]2[C:16]=1[CH:17]=[CH:18][N:19]2C(OC(C)(C)C)=O)([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]#[N:14])=[CH:12][C:6]=2[N:5]=1)[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+]>CO>[NH2:1][C:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]#[N:14])=[CH:12][C:6]=2[N:5]=1)([C:15]1[C:23]([O:24][CH:25]([F:26])[F:27])=[CH:22][C:21]([CH3:28])=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)[CH3:3]
Reactant: Cc1cc(OC(F)F)c(C(C)(N)c2nc3cc(C#N)ccc3[nH]2)c2ccn(C(=O)OC(C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: Cc1cc(OC(F)F)c(C(C)(N)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(1-amino-1-(5-cyano-1H-benzo[d]imidazol-2-yl)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (77 mg, 0.160 mmol) in MeOH (1.6 mL) at room temperature, Cs2CO3 (261 mg, 0.8 mmol) was added and the reaction was stirred at 60° C. After 1 hour the reaction mixture was loaded directly onto a silica gel column and purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.19 (br. s., 1H) 7.96 (br. s., 1H) 7.58 (br. s., 1H) 7.50 (dd, J=8.21, 1.39 Hz, 1H) 7.28 (t, J=2.91 Hz, 1H) 6.70 (s, 1H) 6.66 (t, J=75.3 Hz, 1H) 6.45 (br. s., 1H) 2.45 (d, J=0.76 Hz, 3H) 2.00 (s, 3H). HRMS calcd. for C20H17F2N5O (M+H)+ 382.1474. found 382.1486.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]4[OH:25])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.ClC1N=C(N[C@H]2CCC[C@@H](O)[C@@H]2O)C(F)=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@@H:19]4[OH:25])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](O)[C@H]4O)n3)c3cc(Cl)cnc32)cc1
Agent: O[C@H]1[C@H](O)CCC[C@@H]1Nc1nc(Cl)ncc1F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](O)[C@@H]4O)n3)c3cc(Cl)cnc32)cc1

Procedure:
According to the method for compound 31c, except use compound 33b (0.07 g, 0.26 mmol) to give compound 33c (0.008 g, 0.015 mmol). DME was used as solvent, not acetonitrile. LCMS RT=4.2 (M+1) 532.3, (M−1) 530.3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]#[N:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li].[CH3:19]C(NC(C)C)C.IC>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:19])[C:16]#[N:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(CC#N)cc1OC1CCCC1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(C(C)C#N)cc1OC1CCCC1
Temperature: -78 °C
Yield: 100 %

Procedure:
A mixture of 3-(cylcopentyloxy)-4-methoxybenzeneacetonitrile (20 g) in THF (200 ml) was stirred at -78° C. under a N2 flow. N-(1-methylethyl)-2-propanamine lithium salt (45 ml) was added dropwise and the resulting mixture was stirred for 30 minutes at -78° C. Iodomethane (13.5 g) was added dropwise and the resulting reaction mixture was allowed to warm to RT. The reaction mixture was stirred for 2 hours. The mixture was quenched with a saturated aqueous NH4Cl solution (200 ml) and was extracted with CH2Cl2 (3×φml). The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated, yielding 17.7 g (100%) of (±)-3-(cyclopentyloxy)-4-methoxy-α-methylbenzeneacetonitrile (interm. 8).