Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:24][CH2:25][CH:26]([OH:29])[CH2:27]O)=[CH:16][CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:29][CH:26]([CH2:25][O:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([Cl:13])=[CH:15][CH:16]=2)[CH2:27][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: OCC(O)COc1ccc(Cl)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCCCO
Solvent: O
Product: Clc1ccc(C2(CBr)OCC(COc3ccc(Cl)c4ccccc34)O2)c(Cl)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 15.2 parts of 3-(4-chloro-1-naphthalenyloxy)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The reaction mixture is evaporated and the residue is triturated in 2-propanol. The product is filtered off and crystallized from butanol, yielding A + B 2-(bromomethyl)-4-(4-chloro-1-naphthalenyloxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane; mp. 122.7°C.
Reaction SMILES: OC1C=C(CCC(OCC)=O)C=CC=1.COCOC.[Cl:20]C1C=C(CCC(OCC)=O)C=CC=1.COCOC1C=C(C=CC=1)CC1C(=O)NC(SC)=NC=1.[CH3:54][C:55]1[NH:59][CH:58]=[N:57][C:56]=1[CH2:60][S:61][CH2:62][CH2:63][NH:64][C:65]1[NH:70][C:69](=[O:71])[C:68]([CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([O:79]COC)[CH:74]=2)=[CH:67][N:66]=1>>[ClH:20].[CH3:54][C:55]1[NH:59][CH:58]=[N:57][C:56]=1[CH2:60][S:61][CH2:62][CH2:63][NH:64][C:65]1[NH:70][C:69](=[O:71])[C:68]([CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([OH:79])[CH:74]=2)=[CH:67][N:66]=1
Reactant: COCOc1cccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1
Reactant: CCOC(=O)CCc1cccc(Cl)c1
Agent: CCOC(=O)CCc1cccc(O)c1
Agent: COCOc1cccc(Cc2cnc(SC)[nH]c2=O)c1
Solvent: COCOC
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2cccc(O)c2)c(=O)[nH]1
Product: Cl

Procedure:
Treatment of ethyl 3-(3-hydroxyphenyl)propionate with dimethoxymethane and substitution of the product for ethyl 3-(3-chlorophenyl)propionate in the procedure of Example 4 leads to the production of 5-[3-(methoxymethoxy)benzyl]-2-methylthio-4-pyrimidone and 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-[3-(methoxymethoxy)benzyl]-4-pyrimidone. Treatment of this product with hydrochloric acid gives 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-hydroxybenzyl)-4-pyrimidone.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>O1CCOCC1>[C:19]([CH:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:20]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CC(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
There were gradually added to a cooled and stirred solution of 190 grams of 2,6-dichloro-3-nitropyridine and 117 grams of benzyl cyanide in 2 liters of dioxane under a nitrogen atmosphere 64 grams of sodium hydride (80% in white oil). The reaction mixture immediately turned a deep dark blue color, gradually a finely divided precipitate began to separate out, the temperature rose (with cooling with ice water) to 30° C. After 3 hours the mixture was treated with about 20 ml of ethyl alcohol, stirred for another 20 minutes, then filtered with suction. The deep blue sodium salt was dissolved in 1 liter of water, treated with dilute acetic acid until the color changed. The 2-(α-cyanobenzyl)-3-nitro-6-chloropyridine formed crystallized out in pure form. M.P. 165° C; Yield 146 grams.
Reaction SMILES: C(O[C:4](=[O:31])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:23][C:20]3([CH2:22][CH2:21]3)[N:19](CC3C=CC=CC=3)[CH2:18][CH2:17]2)[N:7]=1)C.[CH:32]([NH2:34])=[O:33].C[O-].[Na+].O.[CH3:39][N:40]([CH:42]=O)C>CO.CCOC(C)=O>[CH2:21]1[C:20]2([CH2:23][N:16]([C:8]3[N:7]=[C:6]([C:5]4[C:4](=[O:31])[NH:34][C:32](=[O:33])[C:14]=4[C:13]4[C:12]5[C:39](=[C:6]([CH3:5])[CH:15]=[CH:10][CH:11]=5)[NH:40][CH:42]=4)[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:17][CH2:18][NH:19]2)[CH2:22]1
Reactant: CCOC(=O)Cc1nc(N2CCN(Cc3ccccc3)C3(CC3)C2)cc2ccccc12
Reactant: NC=O
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cccc2c(C3=C(c4nc(N5CCNC6(CC6)C5)cc5ccccc45)C(=O)NC3=O)c[nH]c12
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
[3-(4-Benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetic acid ethyl ester (700 mg, 1.68 mmol) is dissolved in dry DMF under an atmosphere of argon. Formamide (224 μl, 254 mg, 5.64 mmol) is added, and the reaction mixture is heated to 105° C. At this temperature, NaOMe (312 μl of a 5.4 M solution in MeOH, 91 mg, 1.68 mmol) is added dropwise during 20 minutes. After 30 minutes at 105° C., TLC analysis indicates complete conversion of starting material. Cooling the reaction mixture to RT is followed by addition of water and extraction with EtOAc. The organic layers are washed with H2O (twice), dried over Na2SO4 and concentrated. The residue is purified by FCC (hexanes/EtOAc 1:1 to 1:3 to 0:100 to EtOAc/MeOH 98:2) to afford the title compound. 1H NMR (DMSO, 400 MHz) δ 0.68 -0.70 (m, 2H), 0.82 -0.88 (m, 2H), 3.08 (t, J=4.4, 2H), 3.45 (s, 2H), 3.58 (t, J=4.4, 2H), 3.96 (s, 2H), 4.27 (s, 2H), 5.3 -5.5 (br, 1H), 6.55 -6.7 (br, 1H), 6.72 (s, 1H), 7.26-7.36 (m, 6H), 7.51 (t, J=8.8, 1H), 7.60 d, J=9.9, 1H), 8.02 (d, J=9.9, 1H); ES-MS: 387 [M+H]+.
Reaction SMILES: [C:1]([C:3]([CH3:11])=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[O-])#[N:2].[K+].CCO.Cl.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18]>CCOC(C)=O.O>[CH2:9]([O:8][C:6]([C:4]1[C:3]([CH3:11])=[C:1]([NH2:2])[N:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:22]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C([O-])=C(C)C#N
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C(C)(C)C)c(N)c1C

Procedure:
Placed 47 (1.0 eq.) into a sealed pressure reaction flask. Added EtOH and t-butylhydrazine hydrochloride (1.1 eq.). The pressure flask was capped and heated to reflux. After a time sufficient for reaction completion, the mixture was evaporated to dryness and the solid obtained was dissolved in equal amounts of EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, brine, dried with MgSO4, and evaporated. This slightly yellow solid was triturated with hexanes and filtered to afford ester 48.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:36])[N:13]2[C:16](=[C:30](S(C)(=O)=O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>C1C=CC=CC=1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:36])[N:13]2[C:16](=[C:30]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)S(C)(=O)=O
Solvent: c1ccccc1
Solvent: O
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 2.17 h
Yield: 97.1 %

Procedure:
To a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonylethylidene)acetate (298 mg) in benzene (3 ml) is added morpholine (0.095 ml) at 7° to 10° C. After 130 minutes, the reaction mixture is filtered to give filtrate, which is poured into iced water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)-acetate (284 mg). Foam. Yield: 97.1%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17]([OH:19])=O.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17]([N:20]1[CH2:25][CH2:24][N:23]([C:17]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=3)=[O:19])[CH2:22][CH2:21]1)=[O:19]
Reactant: COc1cc2c(cc(C(=O)O)n2C)c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2c(cc(C(=O)N3CCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
N-Methyl-4,5,6-trimethoxyindole-2-carboxylic acid (200 mg) and piperazine (35 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([NH:16][C:17](=[O:34])[CH:18]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:19][CH3:20])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.Br[CH2:37][CH2:38]Br.C(=O)([O-])[O-].[K+].[K+].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:35])[CH:4]([N:16]1[CH2:38][CH2:37][N:21]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH:18]([CH2:19][CH3:20])[C:17]1=[O:34])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)NC(Cc1ccc2ccccc2c1)C(=O)OC
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1C(=O)N(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 98 %

Procedure:
To a solution of 3-naphthalen-2-yl-2-[2-(2-nitrobenzenesulfonylamino)-butyryl amino]-propionic acid methyl ester, 31, (26.6 g, 53.2 mmol) in anhydrous DMF (100 mL) is added 1,2-dibromoethane (100.0 g, 532.0 mmol) and potassium carbonate (66.1 g, 479.0 mmol). The reaction mixture is heated at 60° C. over night. The reaction mixture is cooled in an ice bath and the pH is adjusted to ˜3 with 1M KHSO4. The reaction mixture is extracted with EtOAc (3×300 mL). The organic layers are combined and washed with water (200 mL), dried over Na2SO4 and concentrated in vacuo and the resulting residue is purified over silica (Hexane: EtOAc 1:1; 5% MeOH in EtOAc) to afford 27.4 g (98% yield) of the desired product. 1H NMR (CDCl3, δ): 8.02–7.90 (m, 1H), 7.84–7.70 (m, 3H), 7.64–7.58 (m, 3H), 7.55–7.50 (m, 1H), 7.50–7.40 (m, 2H), 7.30 (d, J=6.0 Hz, 1H), 5.35 (dd, J−12.0, 4.8 Hz, 1H), 4.25 (t, J=7.2 Hz, 1H, 3.78–3.68 (m, 1H), 3.65 (s, 3H), 3.52 (dd, J=15.0, 6.0 Hz, 1H), 3.30–3.10 (m, 4H), 1.58–1.50 (m, 1H), 1.42–1.38 (m, 1H), 0.56 (t, J=7.2 Hz, 3H); 13C NMR, δ 170.5, 167.8, 148.0, 134.2, 134.0, 133.6, 133.1, 132.6, 132.3, 130.9, 128.5, 127.9, 127.7, 127.5, 126.9, 126.5, 126.0, 124.6.
Reaction SMILES: O.Cl.C1(C)C=CC=CC=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[Br:30]>[Zn].O1CCOCC1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:22]=2)=[CH:13][C:12]=1[Br:30]
Reactant: Nc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1Br
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(CCCC(=O)O)cc2)cc1Br
Yield: 25 %

Procedure:
A mixture of 6 ml of water, 8 gm of amalgamated zinc, 14 ml of concentrated hydrochloric acid, 20 ml of toluene and 4 gm of 4-(4'-amino-3'-bromo-4-biphenylyl)-4-oxo-butyric acid was refluxed for 6 hours, while stirring. Subsequently, 10 ml of dioxane were added and the toluene/dioxane phase was separated. The residue remaining after evaporation of the solvent was admixed with water, covered with ether, and adjusted with sodium bicarbonate solution to pH 6. The ether solution was separated, washed with water, dried over sodium sulfate and evaporated. The thus obtained 4-(4'-amino-3'-bromo-4-biphenylyl)-butyric acid was dissolved in ethyl acetate and converted into its cyclohexylamine salt by addition of cyclohexylamine. Yield: 25% of theory. Melting point of the cyclohexylamine salt: 182° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([S:13][CH2:14][C:15]#[N:16])=[C:7]([C:9](OC)=[O:10])[S:8][C:4]=2[CH:3]=1.O.[OH-].[Li+]>CN(C=O)C.Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[S:13][C:14]([C:15]#[N:16])=[C:9]([OH:10])[C:7]=3[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2cc(Cl)ccc2c1SCC#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1sc2c(sc3cc(Cl)ccc32)c1O
Yield: 43.5 %

Procedure:
A solution of methyl 6-chloro-3-[(cyanomethyl)thio]-1-benzothiophene-2-carboxylate (1.01 g, 3.4 mmol) in DMF (20 mL) was cooled to 0° C., and lithium hydroxide hydrate (171 mg, 1.2 eq) was added in a single portion. After 1h, the solution was warmed to room temperature and stirred for an additional hour. The reaction solution was diluted with aq. hydrochloric acid and ethyl acetate. The organic layer was washed with water and brine, dried, filtered, evaporated, and recrystallized (EtOH) to provide 6-chloro-3-hydroxythieno[3,2-b][1]benzothiophene-2-carbonitrile (393 mg, 43%) as an off-white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH:11]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:34]([C:7]1[CH:8]=[C:9]2[C:14]([CH2:13][CH2:12][CH:11]([NH:17][C:18](=[O:19])[O:20][CH2:21][CH3:22])[CH:10]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:15][CH:16]=1)#[N:35]
Reactant: CCOC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.58 h

Procedure:
8-(3,4-Dichlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (250 mg, 0.475 mmol), zinc cyanide (139 mg, 1.187 mmol) and tetrakistriphenyl palladium (82 mg, 0.071 mmol) in dimethylformamide (5 mL) were heated in the microwave at 120° C. (100 W) under stirring for 35 min. The solvent was evaporated in vacuo and the crude product was partitioned between ethyl acetate (40 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate one more time (20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product (460 mg) was purified by flash chromatography (dichloromethane to dichloromethane:methanol=100:1, silica gel). Yield: 109 mg (0.270 mmo, 57%, colorless solid).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5]([C:6]3[C:7](=[C:11]([C:14]([O:16]CC)=[O:15])[NH:12][CH:13]=3)[NH:8][CH:9]=2)=[N:4][N:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO.C1COCC1.[Li+].[OH-]>O>[O:1]=[C:2]1[C:10]2[C:5]([C:6]3[C:7](=[C:11]([C:14]([OH:16])=[O:15])[NH:12][CH:13]=3)[NH:8][CH:9]=2)=[N:4][N:3]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1[nH]cc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1[nH]cc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c12
Temperature: 45 °C

Procedure:
Ethyl 3-oxo-2-phenyl-2,3,5,7-tetrahydropyrazolo[3,4-d]pyrrolo[3,4-b]pyridine-6-carboxylate was dissolved into a mixture of methanol, THF and H2O (1:1:1, 0.2 M). LiOH (5 eq.) was added and the reaction was heated at 45° C. for 17 hours. After cooling to room temperature the reaction was concentrated to dryness. 10% HCl (aq.) was added and the precipitate was collected, affording the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.87-7.21 (m, 1H) 7.25-7.52 (m, 2H) 7.60-7.85 (m, 1H) 8.13 (br. s., 3H) 11.56-11.92 (m, 1H) 12.90-13.17 (m, 1H)
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH:34]([CH3:36])[CH3:35])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH:34]([CH3:36])[CH3:35])[N:27]=2)[CH:6]=1
Reactant: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc1C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (100 mg, 200 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (456 mg, 308 μL, 4.00 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo then 25% aqueous NH4OH solution added. This was then diluted with dichloromethane and water, the phases separated, and the organic phase washed twice with water. The organic layer was dried over anhydrous magnesium sulfate then purified by chromatography (silica, 0 to 15% methanol in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (43 mg, 108 μmol, 54%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 8.31 (s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 3.80 (s, 3H), 3.42 (m, 1H), 3.15 (s, 1H), 1.52-1.69 (m, 8H), 1.32 (m, 2H), 1.24 (d, J=6.4 Hz, 6H); MS (EI/CI) m/z: 400.3 [M+H].
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][S:11](=[O:27])(=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)C1C=CC=CC=1.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[OH:32][C@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[CH2:30][NH:29][CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][S:11]([CH2:10][C:9]([OH:8])=[O:28])(=[O:26])=[O:27])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)CC(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)CC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from [4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-acetic acid benzyl ester (which was obtained in Example 236) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.05 (m, 2H), 2.50-2.90 (m, 5H), 2.94 (s, 3H), 3.50-3.65 (m, 2H), 4.65-4.75 (m, 1H), 6.80-6.90 (m, 3H), 7.00-7.10 (m, 3H), 7.23 (d, J=2.0 Hz, 1H); MS (ES) m/z: 543.3 (MH+); HRMS Calcd. for C29H37N4O8S2 (MH+): 543.1578. Found: 543.1572.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C@@H:13]([OH:17])[C:14]([OH:16])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:21][C@H:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][C:26]([OH:32])=[CH:27][CH:28]=2)[CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:13]([OH:17])[C:14]([NH:21][C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][C:26]([OH:32])=[CH:27][CH:28]=3)[CH2:23]2)=[O:16])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](O)c1ccc(OCc2ccccc2)cc1
Reactant: N[C@H]1CCc2ccc(O)cc2C1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccc(OCc2ccccc2)cc1
Yield: 91.7 %

Procedure:
(R)-4-Benzyloxymandelic acid (2.43 g), (S)-2-amino-7-hydroxytetralin hydrobromide (2.87 g) and triethylamine (2.88 ml) were dissolved in dichloromethane (38 ml), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4.58 g) was added to the solution at room temperature with stirring. After reaction for 15 hours, ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine successively, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: chloroform/ethyl acetate=1/1) and following recrystallization from ethyl acetate-hexane gave (2R)-2-(4-benzyloxyphenyl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (3.48 g) having a melting point of 137-139° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].[OH-].[Na+].[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][C:14](Cl)=[O:15]>>[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][C:14]([NH:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])=[O:15]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(Cl)CC(F)=C(F)F
Agent: [Na+]
Agent: [OH-]
Product: O=C(CC(F)=C(F)F)NS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 16.4 %

Procedure:
To an ice-cooled solution of trifluoromethanesulfonamide (2.75 g, 18.4 mmol) in 7.4 ml, of 2.5N sodium hydroxide was added 3,4,4-trifluoro-3-butenoyl chloride (2.93 g, 18.5 mmol) with stirring in 2 min. The mixture was stirred in cold for 30 min and the white precipitate formed was filtered, washed with cold water (10 mL) and dried to give 0.82 g (16%) of the desired product as a white solid. m.p. 115°-120° C.
Reaction SMILES: [OH:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].[CH2:7](O)[CH2:8][CH2:9][CH3:10].O>C1C=CC=CC=1>[OH:1][CH:2]([PH:4](=[O:5])[O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3]
Reactant: CCCCO
Reactant: CC(O)[PH](=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCCO[PH](=O)C(C)O
Yield: 81.6 %

Procedure:
A solution of α-hydroxyethylphosphinic acid (2.2 g) and 1-butanol (5.0 g) in benzene (30 ml) was heated for 3 hours with removal of water through a Dean-Stark apparatus. After cooling, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to give 2.71 g (81.6%) of n-butyl α-hydroxyethylphosphinate (Compound No. 5).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[CH:13]2[OH:16])=[CH:4][CH:3]=1
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)C(O)c1cc(Br)ccc1O2
Yield: 88.5 %

Procedure:
To a mixture of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (45 g, 139 mmol) in THF (400 ml) and MeOH (400 ml) at RT was added NaBH4 (10.54 g, 279 mmol) slowly over the course of one hour. The solution was stirred vigorously for 30 additional minutes, then quenched slowly with a saturated ammonium chloride solution (200 ml). Additional water was added and the mixture was filtered, then washed with water and dried under vacuum to afford 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-ol (40 g, 123 mmol) as a light yellow solid that was advanced without further purification.