Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](/[O:20][CH3:21])\[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O.O1CC[CH2:42][CH2:41]1>C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](/[O:20][CH3:21])\[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:41][CH3:42])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(/OC)C(=O)OC)cc2OCCCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(/OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
1.3 mL (1.3 mmol) of aqueous 1 M sodium hydroxide solution are added to a solution of 0.33 g (0.65 mmol) of methyl (E)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 8 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 6 hours. After cooling, the reaction is worked up by addition of 2 mL (2 mmol) of aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 and then 50/50 heptane/ethyl acetate mixture. The product obtained is then recrystallized from isopropyl ether to give 0.25 g (90%) of (E)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a white solid with a melting point of 89° C.
Reaction SMILES: [OH-].[K+:2].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].O>C1(C)C=CC=CC=1>[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[O-:17])([CH3:6])([CH3:5])[CH3:4].[K+:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc([O-])c(C(C)(C)C)c1

Procedure:
4.85 grams of 46.3% aqueous potassium hydroxide was added to a solution of 8.24 grams of 2,4-di-tert.butylphenol in 250 ml of toluene and heated at reflux over a period of about 2 hours until all the water including reaction water was removed by azeotropic distillation yielding a dispersion of the potassium 2,4-di-tert. butylphenolate in toluene. To this dispersion at -5° C. was added a solution of 21.7 grams of the compound of Example 1 in 60 ml of toluene at -5° to -3° C. over a period of 25 minutes and then stirring continued overnight. The reaction mixture was clarified by filtration of the precipitated potassium chloride and the product isolated as a residue by distillation of the toluene at reduced pressures. The product was isolated as crystals after crystallization from a solvent mixture of acetonitrile and toluene yielding white crystals melting at 195°-197° C.
Reaction SMILES: C(S[C:9]1[NH:10][CH2:11][CH2:12][N:13]=1)C1C=CC=CC=1.[CH3:14][CH:15]([CH:17]1[CH2:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]1)[CH3:16]>ClCCl.C1N2CCN(CC2)C1>[CH3:16][CH:15]([CH:17]1[CH2:18][C:19](=[O:24])[C:20](=[C:9]2[NH:13][CH2:12][CH2:11][NH:10]2)[C:21](=[O:23])[CH2:22]1)[CH3:14]
Reactant: c1ccc(CSC2=NCCN2)cc1
Reactant: CC(C)C1CC(=O)CC(=O)C1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CC(C)C1CC(=O)C(=C2NCCN2)C(=O)C1
Reaction time: 7.1 h
Yield: 14.5 %

Procedure:
A mixture of 2-benzylthio-4,5-dihydro-1H-imidazole (15.4 grams, 0.08 mole), 5-(1-methylethyl)-1,3-cyclohexanedione (12.3 grams, 0.08 mole) and 0.11 gram of DABCO is heated at 115°-120° C., with stirring, for a period of 7.1 hours. The cooled residue is dissolved in dichloromethane and the solution extracted with three portions of 3N sodium hydroxide, then with four portions of 3N hydrochloric acid. The organic phase is then dried over magnesium sulfate and evaporated, to give 15.31 grams of crude product as a yellow solid. The material is recrystallized twice from toluene and once from ethyl acetate, to give 2.58 grams of product, m.p. 223°-225° C.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[CH3:32][C@@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:37]2[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=3)=[O:40])[C@H:33]([CH3:32])[CH2:38]2)=[O:29])[CH2:10]1
Reactant: C[C@@H]1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 69.4 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 0.23 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.10 g of N,N'-carbonyldiimidazole and 0.17 g of (2R)-2-methyl-1-(4-nitrobenzyloxycarbonyl)piperazine, 0.21 g of the title compound was obtained as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl>C(O)C>[NH2:22][CH2:21][CH2:20][CH2:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: Cl
Solvent: CCO
Product: NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Temperature: 75 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
tert-Butyl 3-[(11s)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (689 mg, 1.74 mmol) was dissolved in 10 mL of ethanol and 2 mL of a 4.0 M solution of HCl in ethanol was added. The reaction mixture was heated to 75° C. After 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was treated with 25 mL H2O and 20 mL of CHCl3. The layers were separated and the organic portion was discarded. The aqueous layer was then made basic by addition of 5 mL of concentrated NH4OH solution. The aqueous portion was then extracted with CHCl3 (6×10 mL). The combined organic extracts were concentrated under reduced pressure to give (11S)-11-(3-aminopropyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (469 mg) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:27][CH:28]([F:37])[O:29][C:30]1[CH:31]=[CH:32][C:33](Cl)=[N:34][CH:35]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[CH:31][C:30]([O:29][CH:28]([F:37])[F:27])=[CH:35][N:34]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: FC(F)Oc1ccc(Cl)nc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(OC(F)F)cn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-difluoromethoxy-2-chloro-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.18 min; Mass spectrum (ESI+): m/z=502 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].C(OC(=O)C)(=O)C.Cl[C:23](Cl)([F:28])[C:24]([O:26][CH3:27])=[O:25]>[Zn].[Cu]Cl.O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH:13]=[C:23]([F:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: CCOc1ccc(C2(C=O)CC2)cc1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCOc1ccc(C2(C=C(F)C(=O)OC)CC2)cc1
Yield: 62.7 %

Procedure:
The method of Example 1 was repeated using zinc powder (4.1 g), copper (I) chloride (0.63 g), molecular sieve 4A (4.2 g), tetrahydrofuran (72 ml), 1-(4-ethoxyphenyl)-1-formylcyclopropane (4.7 g), acetic anhydride (2.6 ml) and methyl dichloro-fluoroacetate (3.3 g) to yield the title compound (3.4 g, 52%).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH3:13][NH2:14]>C1COCC1.CCOC(C)=O>[CH3:13][NH:14][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(CNC)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of ethyl 2-bromomethylthiazole-4-carboxylate (4.25 g, 17 mmol) in THF (50 ml) was added to a solution of methylamine in THF (2M, 30 ml, 60 mmol) drop-wise while cooling to −10° C. The mixture was allowed to warm to room temperature and stirred for a further 30 min. The mixture was diluted with EtOAc and washed with 0.3N potassium hydrogen sulphate solution and brine. The organic phase was dried and reduced to yield ethyl 2-(methylaminomethyl)thiazole-4-carboxylate (3.06 g, 70%) as an orange oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:14]([CH2:15][C:16]#[N:17])[C:13](=[O:18])[C:12]3[CH:19]=[CH:20][CH:21]=[N:22][C:11]=3[S:10]2)=[CH:4][CH:3]=1.CN(C=O)C.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:14]([CH2:15][C:16]3[NH:30][N:29]=[N:28][N:17]=3)[C:13](=[O:18])[C:12]3[CH:19]=[CH:20][CH:21]=[N:22][C:11]=3[S:10]2)=[CH:4][CH:3]=1
Reactant: N#CCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1Cc1nnn[nH]1

Procedure:
A mixture of 658 mg (2 mmol) of [2-[(4-chlorophenyl)imino]-2,3-dihydro-4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetonitrile and 8 ml of DMF was put in a 50 ml flask. To the mixture were then added 1.30 g of sodium azide and 1.07 g of ammonium chloride with stirring. The mixture was then stirred at a temperature of 120° C. for 4 hours. The resulting reaction mixture was allowed to cool, poured into water, and then extracted with ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then washed with cold ethanol to obtain 512 mg of 2,3-dihydro-[2-((4-chlorophenyl)imino]-3-(1H-tetrazol-5-ylmethyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:7]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[Na].[CH3:23][OH:24]>>[C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12]1[CH:21]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:10][N:11]=1)([O:24][CH3:23])=[O:20]
Reactant: CO
Reactant: COc1ccc(-c2cc3n(n2)C(=O)c2ccccc2-3)cc1
Agent: [Na]
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 2-(4-methoxyphenyl)pyrazolo[5,1-a]isoindol-8-one (100 mg), methanol(10 ml), and sodium (0.1 g), was stirred overnight at 25°. Evaporation of the methanol left 120 mg (96%) of colorless gum which was the ester 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole. The crude ester was dissolved in benzene and stirred overnight with 2 g of Florisil. Filtration and evaporation of the benzene solution, followed by recrystallization from hexane-ethyl acetate (1:1), gave 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole, mp 92°-93°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[C:18]1([NH:24][C:25](=[O:26])[O:14][C:9]2[CH:10]=[C:11]([Cl:13])[CH:12]=[C:7]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:15][CH2:16][CH3:17])[CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(COc1cc(O)cc(Cl)c1)OCC
Reactant: O=C=Nc1ccccc1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(COc1cc(Cl)cc(OC(=O)Nc2ccccc2)c1)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Diethoxyethoxy)-5-chlorophenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-diethoxyethoxy)-5-chlorophenyl] N-phenylcarbamate as the residue.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1.CO.[CH2:39](NCC)C>C(=O)=O>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH3:39])=[O:32])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1
Reactant: CCNCC
Reactant: CC(C)CC(Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: O=C=O
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)nc1

Procedure:
(+/−)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)butylamino)nicotinamido)propanoate (prepared as described in Example 1.29) was resolved via SFC (Column: Chiralcel OJ-H 250×4.6 mm×5 μm, Mobile phase: 5 to 40% methanol in CO2, modifier: 0.05% diethylamine, flow rate: 2.5 mL/min) to give methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)butylamino)nicotinamido)propanoate, Isomer 1 (retention time: 7.36 min) and methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)butylamino)nicotinamido)propanoate, Isomer 2 (retention time: 8.85 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:39]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[NH:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)=[O:25].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:39]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[NH:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Yield: 100 %

Procedure:
tert-Butyl 4-({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)piperidine-1-carboxylate (35 mg, 0.064 mmol) was treated with trifluoroacetic acid (1.0 mL) and methylene chloride (1.0 mL) for 10 minutes and evaporated to give the desired compound (35 mg, 100% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 2H), 9.25 (s, 1H), 8.60 (m, 1H), 8.28 (m, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.75 (s, 1H), 7.20 (d, 1H), 7.05 (m, 2H), 6.91 (d, 1H), 6.77 (d, 1H), 3.38 (m, 2H), 2.80 (m, 7H), 2.01 (m, 2H), 1.82 (m, 2H). LCMS for C24H26ClN6O (M+H)+: m/z=449.2.
Reaction SMILES: C([O-])(=O)C.[K+].C(O)(=O)C.[NH2:10][C:11]1[N:12]=[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])[NH:14][C:15]=1[C:16]#[N:17].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>ClCCl>[CH2:18]([C:13]1[NH:14][C:15]([C:16]#[N:17])=[C:11]([N:10]2[CH:24]=[CH:28][CH:27]=[CH:26]2)[N:12]=1)[CH2:19][CH2:20][CH3:21]
Reactant: COC1CCC(OC)O1
Reactant: CCCCc1nc(N)c(C#N)[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nc(-n2cccc2)c(C#N)[nH]1
Temperature: 25 °C

Procedure:
A solution of potassium acetate (5.0 g), acetic acid (22 mL) and 4-amino-2-butyl-5-cyanoimidazole (Example 7, 1.45 g) was heated to reflux and treated with 2,5-dimethoxy-tetrahydrofuran (1.25 mL). The reaction was held at reflux for 1 minute then cooled back to room temperature with an ice bath. The majority of the acetic acid was evaporated at reduced pressure then the residue was partitioned between ethyl acetate and 10% aqueous K2CO3 (120 mL) each. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (90:10 to 80:20). Evaporation of solvents gave a gum that was redissolved in dichloromethane and evaporated once again. The residual oil was held under a vacuum overnight to afford a waxy solid. 1H-NMR (CDCl3) δ9.9 (br, 1H), 7.4 (s, 2H), 6.3 (s, 2H), 2.7 (t, 2H), 1.7 (m, 2H), 1.4 (m, 2H), 1.0 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.Br[CH2:37][CH2:38][OH:39]>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:37][CH2:38][OH:39])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: OCCBr
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(CCO)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (400 mg, 1.0 mmol) in tetrahydrofuran (14 mL) was treated with triethylamine (350 μL, 2.5 mmol) and 2-bromoethanol (85 μL, 1.2 mmol) and stirred at 60° C. overnight. The reaction mixture was concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.14 g, 31%). The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.46 (s, 1H), 6.24 (q, J=6.9 Hz, 1H), 4.41 (t, J=5.4 Hz, 1H), 4.12-4.03 (m, 1H), 3.97-3.88 (m, 2H), 3.64 (s, 3H), 3.38-3.34 (m, 2H), 3.09-3.01 (m, 2H), 2.55 (s, 3H), 2.41 (t, J=5.9 Hz, 2H), 1.72 (d, J=7.0 Hz, 3H). LCMS for C21H25ClN7O2 (M+H)+: m/z=442.2; Found: 442.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:27]=[CH:26][C:15]4[N:16](C(OC(C)(C)C)=O)[N:17]=[N:18][C:14]=4[CH:13]=3)[C:6]=2[N:7]=1.C1COCC1.CNC>CO>[NH:16]1[C:15]2[CH:26]=[CH:27][C:12]([CH2:11][N:8]3[C:6]4[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:28]5[O:29][CH:30]=[CH:31][CH:32]=5)[C:5]=4[N:10]=[N:9]3)=[CH:13][C:14]=2[N:18]=[N:17]1
Reactant: CC(C)(C)OC(=O)n1nnc2cc(Cn3nnc4c(-c5ccco5)nc(N)nc43)ccc21
Agent: CNC
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(-c2ccco2)c2nnn(Cc3ccc4[nH]nnc4c3)c2n1
Yield: 30 %

Procedure:
A solution of tert-butyl 5-(5-amino-7-(2-furyl)-3H-triazolo[4,5-d]pyrimidin-3-yl)methyl-1H-benzotriazol-1-carboxylate (as a mixture with the 6-substituted regioisomer) (135 mg, 0.31 mmol) in MeOH (5 mL) and THF (5 mL was treated with 40% aqueous dimethylamine (0.176 mL, 1.56 mmol), refluxed for 25 min, concentrated in vacuo and the resulting solid triturated with ether, filtered, triturated with MeOH, filtered and dried to give the title compound (31 mg, 30%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([Cl:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[C:9]([Cl:15])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(Cl)cc(N)c1Cl
Temperature: 80 °C
Yield: 86.7 %

Procedure:
To stirred solution of methyl 2,5-dichloro-3-nitrobenzoate (3.3 g, 13.1 mmol) in ethanol (20 mL) was added ammonium chloride (3.5 g, 64.81 mmol) dissolved in water (20 mL) and iron powder (7 g, 82.35 mmol). The reaction mixture was heated at 80° C. for 3 h. On completion, water was added to the reaction mixture and the solids removed by filtration through celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with water, dried, and concentrated under reduced pressure to give methyl 3-amino-2,5-dichlorobenzoate (2.5 g, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(#N)C.[CH:15](O)=[O:16]>>[CH:15]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:16]
Reactant: O=CO
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=CNNc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 91 %

Procedure:
46 g of 4-nitrophenylhydrazine was added to 160 ml of acetonitrile, and 32.2 g of formic acid was slowly added thereto at a temperature of 60° C. The reaction mixture immediately turned homogeneous and then crystals were again precipitated. The reaction was continued for an additional 2 hours at a temperature of 80° C., followed by cooling. The precipitated crystals were filtered, washed with acetonitrile and dried to obtain 49.5 g of 1-formyl-2-(4-nitrophenyl)hydrazine. Melting Point: 184°-186° C.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1)=[O:5])[CH2:2][CH3:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.N>[CH2:1]([S:4]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([NH2:13])[CH:7]=1)=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCS(=O)c1ccc(N)c(N)c1
Yield: 59.8 %

Procedure:
To a solution of 6.84 g (0.03 mol) of 4-(1-propylsulfinyl)-2-nitroaniline in 100 ml ethanol is added 18.02 g (0.103 mol) sodium hydrosulfite in 100 ml water and 22 mg concentrated aqueous NH3. The resulting solution is heated to reflux for 1 hour, cooled, alcohol stripped and the aqueous layer extracted with CH2Cl2. The organics are combined, dried, filtered and evaporated in vacuo to yield 3.56 g of 4-(1-propylsulfinyl)-1,2-diaminobenzene in the form of an oil, 60% yield.