Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[C:9]([OH:24])[C:8]2[CH2:25][N:26]([C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH2:27][C:7]1=2.C([O-])([O-])=O.[Na+].[Na+].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC(N(C)C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]2[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[C:9]([OH:24])[C:8]3[CH2:25][N:26]([C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH2:27][C:7]2=3)[CH:3]=1
Reactant: C=CCCC(=O)N1Cc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(Cc3cccc(Br)c3)c2C1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCCC(=O)N1Cc2c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc3cccc(-c4ccccc4)c3)c2C1
Temperature: 115 °C

Procedure:
tert-Butyl N-{[1-(3-bromobenzyl)-4-hydroxy-2-oxo-6-pent-4-enoyl-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-3-yl]carbonyl}glycinate (50 mg, 0.09 mmol, prepared in similar fashion to Intermediate 5 (compound 5-1) was dissolved in DMA (2 mL) in a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor. Aqueaous Na2CO3 (2 M, 0.8 mL, 1.6 mmol), phenylboronic acid (20 mg, 0.16 mmol) and bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.009 mmol) were added and the tube was purged with nitrogen, capped and inserted into the microwave reactor and heated at 115° C., for 15 min. The reaction was diluted with EtOAc, washed with 2 M HCl, dried (Na2SO4), filtered and concentrated. The residue was purified on a C-18 reverse phase chromatography column eluted with 0-100% MeCN in water. The desired fractions were concentrated, diluted with EtOAc and washed with 2 M HCl. The organic portion was isolated, dried (Na2SO4), filtered and concentrated affording the title compound, E43-1. HPLC/MS: 501.9 (M+1); Rt=3.22 min.
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([O:7][C:8]([NH:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=2)(=[O:27])=[O:26])[CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH:5]=[CH2:6].[OH-].[Na+]>C(O)C>[CH2:4]([O:7][C:8]([NH:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=2)(=[O:27])=[O:26])[CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH:5]=[CH2:6]
Reactant: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc(N)c2)c1
Yield: 55.1 %

Procedure:
43.5 g of tin-(II) chloride were added to a solution of 17.8 g of ethyl 3-{[(allyloxy)-carbonyl]-amino}-3-{{3-{[(3-nitrophenyl)-sulfonyl]-amino}-phenyl}}-propanoate from Example II.2.e in 165 ml of ethanol, and the mixture was heated to reflux for a period of time of 2 h. The reaction mixture was hydrolized with 200 ml of aqueous 2N sodium hydroxide solution, then filtered through silica gel and washed with dichloromethane. The organic phase was dried over magnesium sulphate and concentrated to yield 9.2 g of a solid.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:34]1([C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[NH:41][CH2:42][CH2:43][CH2:44]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[O:19][CH2:44][CH2:43][CH2:42][NH:41][C:40]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2cc(-c3ccc(OCCCNC(c4ccccc4)(c4ccccc4)c4ccccc4)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1

Procedure:
360 mg (12 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a three-necked round-bottomed flask. A solution of 4.1 g (10 mmol) of methyl 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoate in 75 ml of DMF are added dropwise, under a nitrogen stream, and the mixture is stirred until the evolution of gas ceases. A solution of 42 g (11 mmol) of N-triphenylmethyl-3-bromopropylamine in 50 ml of DMF is then introduced dropwise and the mixture is stirred at room temperature for 8 h. The reaction medium is poured into water, extracted with ethyl ether, the organic phase separated after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by silica chromatography, eluted with a dichloromethane and hexane mixture (40-60). After evaporation of the solvents, 4.7 g (66%) of the expected product are recovered, which product melts at 168°-9° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18][C:13]=3[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[F:24][C:25]1[CH:26]=[C:27]([F:35])[C:28]2[CH2:29][C@H:30]3[O:34][C@H:31]3[C:32]=2[CH:33]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[F:35][C:27]1[CH:26]=[C:25]([F:24])[CH:33]=[C:32]2[C:28]=1[CH2:29][C@@H:30]([OH:34])[C@@H:31]2[N:12]1[C:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][C:14]=2[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:22])[F:23])[CH:5]=2)=[N:11]1
Reactant: Fc1cc(F)c2c(c1)[C@@H]1O[C@@H]1C2
Reactant: CC(=O)N1CCc2[nH]nc(-c3cccc(OC(F)(F)F)c3)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCc2c(c(-c3cccc(OC(F)(F)F)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Temperature: 50 °C
Reaction time: 24 h
Yield: 23.3 %

Procedure:
A mixture of 1-[3-(3-trifluoromethoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (3e) (0.461 mmol), 0.44 g, 2.65 mmol), (1aS,6aR)-3,5-difluoro-6,6a-dihydro-1aH-1-oxa-cyclopropa[a]indene (6b) (0.077 g, 0.461 mmol) and K2CO3 (127 mg, 0.922 mmol) in 5 ml CH3CN was stirred at 50° C. for 24 h. Water was added, the mixture was extracted 3 times with CH2Cl2, the combined organic layers were dried over MgSO4, filtrated and the solution was evaporated to dryness. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 53 mg of 1-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-3-(3-trifluoromethoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (11a).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].CCN(CC)CC.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.ClCCl>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cn2ncc(C#N)c(NC3CCCCC3)c2c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a solution of compound 1D (20 mg, 0.076 mmol) in acetonitrile (1 mL) were added Et3N (32 μL, 0.228 mmol) and cyclohexylamine (10 μL, 0.084 mmol) and the reaction mixture was stirred at 25° C. After 24 h, an additional 10 μL of cyclohexylamine was added and the reaction mixture was stirred for an additional 1.5 h after which time it was poured onto NaHCO3 (sat. aq., 20 mL) and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers were washed with water (20 mL), dried over MgSO4, filtered and concentrated in vacuo to yield 18 mg (75%) of compound 1E as a yellow solid, which was used without further purification. HPLC: 100% at 4.60 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 327.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([O-:22])=O)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[C:24]([NH:28][C:20]([C:18]1[N:19]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[S:16][CH:17]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nc(C(=O)[O-])cs2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1csc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 53.4 %

Procedure:
To a solution of sodium 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-thiazole-4-carboxylate (3.596 g, 10.29 mmol), tert butylamine (0.753 g, 10.29 mmol, 1.082 mL) and triethylamine (3.12 g, 30.9 mmol, 4.29 mL) in dichloromethane (50 mL) was added 1-propanephosphonic acid cyclic anhydride (13.10 g, 20.58 mmol, 12.25 mL, 50% solution in ethyl acetate. The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with sodium bicarbonate (×3) and brine. The organic phase was concentrated under reduced pressure to afford the title compound (2.10 g). MS (ESI) m/z 283.5 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[N:28]([CH2:29][C:30](=[O:38])[NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:27]2[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:26]=2[N:25]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:23][C:24]3[N:28]([CH2:29][C:30](=[O:38])[NH:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:27]4[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:26]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: N#Cc1ccc2c(c1)nc(CCl)n2CC(=O)NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3nc4cc(C#N)ccc4n3CC(=O)NC3CCCCC3)cc2)CC1
Yield: 95.5 %

Procedure:
A solution of 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (8.21 g), 2-chloromethyl-1-(cyclohexylcarbamoylmethyl)-5-cyanobenzimidazole (9.29 g) and diisopropylethylamine (9.8 ml) in dimethylformamide (93 ml) was stirred at 60° C. for 14 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. To the obtained residue were added ethyl acetate and hexane and the precipitated solid was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give the title compound (15.726 g).
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:5].[CH2:26]([C:29]1[CH:34]=[C:33]([CH:35]=O)[CH:32]=[CH:31][N:30]=1)[CH2:27][CH3:28].CO>O1CCCC1.CN(C)C=O>[CH2:26]([C:29]1[CH:34]=[C:33]([CH:35]=[CH:6][C:4]#[N:5])[CH:32]=[CH:31][N:30]=1)[CH2:27][CH3:28]
Reactant: CCCc1cc(C=O)ccn1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1cc(C=CC#N)ccn1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a suspension of 1.39 g (0.03 mol) sodiumhydride in 40 ml tetrahydrofurane and 40 ml dimethylformamide were added 10.13 g (0.03 mol) (cyanomethyl)triphenylphosphonium chloride. After sirring for 1 hour at room temperature a solution of 4.48 g (0.03 mol) 2-propyl-4-pyridinecarboxaldehyde in 15 ml tetrahydrofuran were added and stirring was continued for 15 hours. Then 10 ml methanol were added) the solvents were evaporated and the residue chromatographed on aluminiumoxide with dichloromethane to yield 2.42 g 3-(2-propyl-pyridin-4-yl)-acrylonitrile as yellow oil. MS m/e (%): 173 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.[Br:19]Br>C1C=CC=CC=1>[Br:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[O:10]
Reactant: BrBr
Reactant: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1Cl)C(Br)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
Part C: To a solution of 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone (5.00 gram, 15 mmol) in benzene (50 mL) is dropwise added bromine (0.75 mL, 15 mmol) and the resulting solution is stirred for 4 hours at room temperature and concentrated in vacuo. Dichloromethane is added and the resulting solution is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2-bromo-2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone as an oil (5.96 gram, 94% yield).
Reaction SMILES: [CH:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=O)[CH2:7][C@@H:6]1[OH:25])([CH3:3])[CH3:2].[C:26]1([CH3:37])[CH:31]=[CH:30][C:29]([S:32]([NH:35][NH2:36])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(O)C>C(Cl)Cl>[S:32]([NH:35][N:36]=[C:15]1[CH2:14][CH2:13][C@H:12]2[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:21]1([CH3:23])[C@H:8]([CH2:7][C@H:6]([OH:25])[C@@H:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH2:22]1)[CH2:9][CH2:10]3)([C:29]1[CH:28]=[CH:27][C:26]([CH3:37])=[CH:31][CH:30]=1)(=[O:33])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CC(C)O[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OC(C)C)C[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 107.7 %

Procedure:
To a mixture of 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one (700 mg, 2.0 mmol) and p-toluenesulfonhydrazide (450 mg, 2.4 mmol) was added ethanol (2 mL) and the mixture obtained was heated to reflux for 12 h. Then the reaction mixture was dissolved in CH2Cl2 (150 mL) and washed with water (4×45 mL). It was then dried over Na2SO4 and removal of the solvent in vacuo resulted in the crude 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one tosylhydrazone (1.113 g), which was used without further purification for the next step.
Reaction SMILES: [NH:1]([C:5]1[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][C:6]=1[CH2:7][N:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:9])C(C)=O.C(O)C.Cl.N>O>[NH2:1][C:5]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:6]=1[CH2:7][N:8]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH3:9]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(CN(C)C2CCCCC2)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CN(Cc1cc(C(=O)O)ccc1N)C1CCCCC1

Procedure:
A mixture of 21 gm of 2-acetamino-5-carbethoxy-N-cyclohexyl-N-methyl-benzylamine, 100 ml of ethanol, 90 ml of water and 60 ml of concentrated hydrochloric acid was refluxed for 1 hour. Thereafter, the reaction solution was cooled, poured over ice, made alkaline with ammonia and extracted three times with chloroform. The aqueous alkaline phase was evaporated to dryness in vacuo, the residue was thoroughly stirred with ethanol, and the mixture was filtered. The filtrate was evaporated to dryness in vacuo, and the residue was recrystallized from ethanol, yielding 2-amino-5-carboxy-N-cyclohexyl-N-methyl-benzylamine, m.p. 200°-205° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=1.[CH3:18][NH2:19]>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=[C:2]([NH:19][CH3:18])[N:7]=1
Reactant: Clc1nc(Cl)nc(N2CCc3ccccc32)n1
Reactant: CN
Solvent: ClCCl
Product: CNc1nc(Cl)nc(N2CCc3ccccc32)n1
Yield: 82 %

Procedure:
To a mixture of 2,4-dichloro-6-indolin-1-yl-1,3,5-triazine (30 g, 112 mM) and methylene chloride (300 ml) at 0° C. was added a 33% solution of methylamine (30 ml) in IMS. The mixture was allowed to attain ambient temperature. After two days the mixture was washed with water. The methylene chloride layer was separated, dried (MgSO4), and the solvent evaporated. The resultant solid was recrystallised from toluene: ethanol (70:30). There was thus obtained 2-chloro-4-indolin-1-yl-6-methylamino-1,3,5-triazine (24 g, 82% yield). m.p 239°-240° C.; NMR: DMSOd6 : 2.75-2.95 (3H, complex, rotamers, NHMe), 3.05-3.2 (2H, t,CH2 --CH2N--), 4.0-4.2 (2H,q,CH2CH2N) (rotamers), 6.9-7.3(3H, complex, aromatic), 7.9-8.1 (1H, broad, aromatic), 8.1-8.4(1H, broad, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][S:24]([CH3:23])(=[O:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cnccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 4-(benzyloxy)pyridin-3-amine (6.2 g, 15.8 mmol), triethylamine (11 mL, 79 mmol), and dichloromethane (163 mL) was added methanesulfonylchloride (1.2 mL, 15.8 mmol) in dichloromethane (100 mL) drop wise over 90 min. The solution was maintained at room temperature for 6 h and concentrated to afford N-(4-(benzyloxy)pyridin-3-yl)methanesulfonamide which was used without further purification. LCMS: retention time: 1.305 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Xterra, 5 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 279 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:33]=[C:18]4[C:19]([O:23]CC5C=CC=CC=5C#N)=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:33]=[C:18]4[C:19]([OH:23])=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(Nc3nc4c(OCc5ccccc5C#N)cccn4n3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(Nc3nc4c(O)cccn4n3)cc2)CC1
Reaction time: 3 h

Procedure:
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ol was prepared from combining 2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl}-benzonitrile (30.0 mg, 0.68 mmol) and 10% palladium on carbon (50% Wet)(5:45:50, palladium:carbon black:water, 30 mg, 0.14 mmol) in methanol (10.0 mL) and shaking under an atmosphere of Hydrogen (45 psi) for 3 hours. Product was isolated as a mustard colored solid (14.0 mg, 63%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.45 (bs, 1H), 9.12 (s, 1H), 8.21 (dd, J=6.4 Hz, 1.0 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 6.80-6.76 (m, 2H), 3.04-3.02 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H). MS=325.2 (MH)+.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12]C(=O)OCCCC)=[CH:4][N:3]=[CH:2]1.[ClH:20]>O1CCOCC1>[Cl-:20].[NH3+:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[N:1]=[CH:2][NH2+:3][CH:4]=1.[Cl-:20]
Reactant: CCCCOC(=O)Nc1ccccc1-c1cnc[nH]1
Reactant: Cl
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]c1ccccc1C1=C[NH2+]C=N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
To a stirred solution of tent-butyl 2-(1H-imidazol-5-yl)phenylcarbamate (64.7 mg, 0.25 mmol) in 1,4-dioxane (2 mL) was added HCl (2 mL, 2.0 M in 1,4-dioxane). The mixture was allowed to stir at room temperature for 12 h and concentrated under reduced pressure. The residue was diluted with ethyl ether and the desired hydrochloride salt was precipitated. The colorless solid was collected by filtration, which afforded the desired product in 46% yield. 1H NMR: 6.66-6.82 (m, 2H), 7.11-7.20 (m, 2H), 7.21-7.38 (m, 4H), 7.40-7.68 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4](O)[N:3]=1.[OH-:9].[K+].[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Br)[C:15]([O:17][CH3:18])=[O:16]>C(O)C.CN(C)C=O>[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:9][C:5]1([CH3:7])[CH:6]=[C:2]([CH3:1])[N:3]=[N:4]1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: Cc1cc(C)n(O)n1
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CON=C(C(=O)OC)c1ccccc1COC1(C)C=C(C)N=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
2.2 g (0.02 mol) of 3,5-dimethyl-1-hydroxypyrazole in 30 ml of ethanol are added dropwise to a solution of 1.2 g (0.02 mol) of potassium hydroxide in 50 ml of ethanol. The reaction mixture is stirred at room temperature for two hours and then concentrated. The residue is taken up in 60 ml of dimethylformamide, and 5.7 g (0.02 mol) of methyl 2-bromomethylphenylglyoxylate O-methyloxime in 30 ml of dimethylformamide are added. The mixture is stirred at 100° C. for two hours, the solvent is removed under reduced pressure, and the residue is taken up in methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 3.7 g (59%) of the title compound are obtained as an oil (compound no. 28).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:5]2.[C:18]1([NH:24][CH2:25][CH2:26][OH:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH2:14][C:15]([N:24]([CH2:25][CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])=[O:12])=[CH:5]2
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: OCCNc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(=O)N(CCO)c1ccccc1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of N-[(5-chloro-1H-indol-2-yl)carbonyl]glycine (Cas Reg No 186429-62-9; Hulin, Bernard, et al, PCT International Patent Application (1996) WO 9639384; 374 mg, 1.5 mmol) and 2-(phenylamino)ethanol (228 mg, 1.6 mmol) in THF (20 ml) was stirred at ambient temperature for 30 minutes. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)4-methylmorpholinium chloride (DMTMM) (480 mg, 1.6 mmol) was added and the reaction mixture stirred at ambient temperature overnight, poured into water (15 ml) and extracted with ethyl acetate (3×15 ml). The organic extracts were combined and washed with 1N citric acid solution (15 ml), sodium bicarbonate solution (15 ml), dried over magnesium sulphate, filtered and concentrated to give the title product (471 mg, 86%).