Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][CH2:12]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[I:19]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Si:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][I:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC#CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC#CCI
Yield: 71.4 %

Procedure:
1-(tert-Butyldimethylsilyloxy)-but-2-yn-4-ol (63, 4.0 g, 19.96 mmol), imidazole (1.80 g, 26.45 mmol), iodine (6.58 g, 25.95 mmol) and triphenylphosphine (6.80 g, 25.95 mmol) are treated in 100 ml dichloromethane according to J. Robertson et al. J. Chem. Soc., Perkin Trans. 1, 3389-3369, 2000. Work-up yields 4.42 g (71%) of a colourless oil. The product is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:12][CH2:13][CH2:14][CH2:15][S:16]([O:8][N:7]=[C:6]([Cl:9])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(C(Cl)=NO)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(Cl)=NOS(=O)(=O)CCCCl)cc1
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a solution of 8.5 g of 4-methylbenzohydroximoyl chloride and 8.8 g of 3-chloropropanesulfonyl chloride in 175 ml of benzene, 7.6 g of triethylamine was added dropwise during 8 minutes. The temperature of the reaction mixture rose to 35°. The reaction mixture was stirred for 1 hour and filtered, the filtrate was evaporated under reduced pressure, and the product was recrystallized twice from ethanol to give 8.4 g of N-(3-chloropropanesulfonyloxy)-4-methylbenzimidoyl chloride, m.p. 56°-58°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:9]=[CH:10]N(C)C)[C:5]([O:7][CH3:8])=[O:6].[CH2:15]([N:17]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18]1)[CH3:16]>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH2:15]([N:17]1[C:21]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[N:9]=[CH:10][C:20]=2[C:19]([CH3:22])=[CH:18]1)[CH3:16]
Reactant: CCn1ccc(C)c1
Reactant: COC(=O)C(=CN(C)C)N=CN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCn1cc(C)c2cnc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.8 %

Procedure:
In a 500 ml round bottom flask, methyl 3-(dimethylamino)-2-((dimethylamino)methyleneamino)acrylate (1A, 12 g, 61 mmol) was dissolved in acetic acid (45 ml) and TFA (15 ml). 1-Ethyl-3-methyl-1H-pyrrole (6.7 g, 61 mmol) was added and the mixture was stirred at room temperature for an hour and then at 110° C. for 4 hours. Volatiles were then evaporated from the reaction mixture, the residue was cooled in an ice bath and ice cold saturated K2CO3 solution (˜200 ml) was slowly added to it. The mixture was extracted with EtOAc (3×250 ml). Combined organic layers were then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on a silica column using hexane-EtOAc (0-100%). Pure fractions were combined and evaporated to give the product methyl 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1N, 6.1 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 1.34 (t, J=7.20 Hz, 3H) 2.34 (d, J=1.01 Hz, 3H) 3.88 (s, 3H) 4.26 (q, J=7.24 Hz, 2H) 7.48 (d, J=1.01 Hz, 1H) 8.20 (d, J=1.01 Hz, 1H) 8.85 (d, J=1.01 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:55][C:56]1(C)[CH2:60]C(=O)[O:58][C:57]1=[O:62]>C(OCC)(=O)C>[CH3:55][C:56]([CH3:60])([CH2:2][C:1](=[O:3])[O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])[C:57]([OH:62])=[O:58]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((1R,3S)-3-(morpholinomethyl)cyclopentylcarbamoyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 23, 0.15 g, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 1H); 2.77-3.58 (m, 11H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: [M+1] 750 (100%); HPLC: 98.08%.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O=[C:7]1[NH:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]2[S:19][C:20]([CH3:22])=[CH:21][C:8]1=2.CN(C)C1C=CC=CC=1>>[Cl:3][C:7]1[C:8]2[CH:21]=[C:20]([CH3:22])[S:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(=O)[nH]c(-c3cccnc3)nc2s1
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1

Procedure:
The replacement of the keto group by Cl under the formation of the aromatic pyrimidine ring takes place under standard conditions. A mixture of POCl3 (18 ml) with 3,4-dihydro-4-oxo-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine (6 g) is refluxed for 4 hours under the addition of N,N-dimethylaniline (1,8 m). The usual workup yields 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine (5 g)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:21]([O:23]C)=O)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25]([NH2:27])[CH3:26]>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:21]([NH:27][CH2:25][CH3:26])=[O:23])[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Reactant: CCN
Product: CCNC(=O)c1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-chloro-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine-9-carboxylate (11-2) (80 mg, 0.235 mmol) and ethylamine (2M in THF, 5 mL, 10 mmol) was stirred at room temperature for overnight. The solvent was evaporated and the residue was purified by column chromatography eluting with 0-20% EtOH in EtOAc to give 3-chloro-N-ethyl-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine-9-carboxamide (11-3).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:21])[C@@H:10]([CH:11](Br)[C:12](=O)CBr)[C@H:9]1[C:17]([O:19][CH3:20])=[O:18].O>O1CCCC1>[CH3:7][C:8]1([CH3:21])[C@@H:10](/[CH:11]=[CH:12]\[C:1]([OH:3])=[O:4])[C@H:9]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@@H]1[C@H](C(Br)C(=O)CBr)C1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Reaction time: 1.5 h

Procedure:
1 ml of a 1N solution of potassium carbonate was placed under an inert gas atmosphere and then a solution of 0.342 g of methyl (1R,cis) 2,2-dimethyl-3-(1,3-dibromo-2-oxopropyl)-cyclopropane-1-carboxylate in 1.5 ml of tetrahydrofuran was added at about +5° C. The mixture was stirred for 90 minutes and then the temperature was allowed to rise to 20° C. and stirring was continued for 4 hours. Water was added and extraction was carried out with methylene chloride. The organic phase was dried and the solvent was evaporated. The residue was chromatographed on silica, eluting with a methylene chloride - ethanol mixture (97-3) to obtain 0.046 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH3:19])=[CH:12][CH:11]=2)[C:5]([C:28]#[N:29])=[C:4]([SH:30])[N:3]=1.Cl[CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])[CH3:19])=[CH:14][CH:15]=2)[C:5]([C:28]#[N:29])=[C:4]([S:30][CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])[N:3]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCl
Reactant: C[C@@H](COc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(F)cc2)nc1CSc1nc(N)c(C#N)c(-c2ccc(OC[C@H](C)O[Si](C)(C)C(C)(C)C)cc2)c1C#N

Procedure:
100 mg (0.18 mmol) of the compound from Example 7A, 45 mg (0.20 mmol) of 4-(chloromethyl)-2-(4-fluorophenyl)-5-methyl-1,3-oxazole and 46 mg (0.55 mmol) of sodium bicarbonate in 2 ml of dry DMF are stirred at RT for 20 h. The mixture is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Removal of the solvent on a rotary evaporator gives the product as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[S:13][CH:14]=[CH:15][C:4]=2[CH:3]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[S:13][CH:14]=[CH:15][C:4]=2[CH:3]=1
Reactant: CC1c2ccccc2Sc2sccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=Cc2ccsc2Sc2ccccc21

Procedure:
24.8 g (0.1 mole) of 4,5-dihydro-5-methyl-benzo[f]thieno [2,3-b]thiepin-4-ol in 600 ml of benzene is boiled, with the addition of 0.57 g (0.03 mole) of p-toluenesulphonic acid hydrate, for one hour on a water separator. The solution is thereupon cooled to 20°, extracted by shaking with 2 N sodium bicarbonate solution, dried over sodium sulphate and concentrated in vacuo. The oily residue is chromatographed on a silica-gel column (300 g of silica gel, particle size 0.063-0.2 mm) with the use of cyclohexane as the eluant. Recrystallisation of the eluted substance from pentane yields 5-methyl-benzo[f]thieno[2,3-b]thiepin, m.p. 70°-71°.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[C:10]1[N:11]=[C:12]([O:36][CH3:37])[C:13]([N:16](COCC[Si](C)(C)C)[S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])(=[O:19])=[O:18])=[N:14][CH:15]=1>>[Cl:27][C:21]1[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:13]1[C:12]([O:36][CH3:37])=[N:11][C:10]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]2)=[CH:15][N:14]=1)(=[O:19])=[O:18]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: OCC1CCNCC1
Product: COc1nc(N2CCC(CO)CC2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 55 using 4-(hydroxymethyl)piperidine (0.4 g) and N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.3 g). Yield 0.012 g.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11](/[CH:29]=[CH:30]/[C:31]([O:33]C(C)(C)C)=[O:32])[CH:12]=[CH:13][C:14]=1[C:15](=[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])[CH:12]=[CH:13][C:14]=1[C:15](=[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 73 (300 mg, 0.706 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was chromatographed on silica gel (20:1 CH2Cl2:MeOH) to afford 225 mg (86%) of 74 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (br s, 6H), 1.88 (br s, 2H), 2.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H). LRMS (ESI): m/z 370 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[O:1]([CH2:8][CH2:9][C:10]([NH:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:24][CH2:25]2)=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCOc1ccccc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(CCOc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use 3-phenoxypropionic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (52% yield). 1H NMR (300 MHz, CDCl3) δ 10.08, 8.40, 7.74, 7.61, 7.55, 7.34, 7.26-7.22, 7.05, 6.93, 6.88, 4.34, 4.01-3.96, 3.92-3.86, 3.68-3.60, 3.55-3.53, 3.29-3.27, 3.08. MS (ES+) m/z 500.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[CH2:35][CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1)#[N:2].[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:38][CH:39]1[CH2:40][CH2:41]1)[CH2:35][CH2:36][CH3:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1)#[N:2]
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Ethyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (240 mg) is dissolved in tetrahydrofuran (2.6 ml), and thereto is added 1N-aqueous sodium hydroxide solution (2.6 ml) and the mixture is stirred at 40° C. for additional 30 minutes and warmed to 50° C. and stirred for 3 hours. Thereto is added a 2N-aqueous sodium hydroxide solution (650 μl) and the mixture is stirred at 60° C. for 20 minutes. The reaction solution is cooled to room temperature and thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=19:1) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (189 mg). MS (m/z): 650 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:21]#[N:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:28]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:21]#[N:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: N#CC(=NOS(=O)(=O)c1ccc(O)cc1)c1cccs1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(S(=O)(=O)ON=C(C#N)c2cccs2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
2.2 g (0.022 mole) of triethylamine and 0.5 g of 4-dimethylaminopyridine are added to a solution of 6.1 g (0.022 mole) of α-(4-hydroxybenzenesulfonyloxyimino)thien-2-ylacetonitrile (3a) in 75 ml of methylene chloride. With cooling to 0° C., a solution of 2.3 g (0.022 mole) of methacryloyl chloride in 20 ml of CH2Cl2 is added dropwise, and the reaction mixture is stirred for 3 hours at 0° C. The mixture is then filtered through silica gel, the filtrate is concentrated by evaporation, and the residue is recrystallised from methylene chloride/hexane, affording 5.92 g of the title compound with a melting point of 165°-166° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18](OC(=O)C)(=O)[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:17])[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:18]([CH3:19])[O:1]2)=[CH:4][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Yield: 66 %

Procedure:
1-(2,4-Dihydroxy-phenyl)-2-phenyl-ethanone (0.5 g, 3.2 mmol) was refluxed in anhydrous DMF with acetic anhydride (1.5 ml), and anhydrous potassium carbonate (1.4 g 10.1 mmol) for 3 hrs. The solution was then poured into water and the precipitate filtered to give 7-hydroxy-2-methyl-3-phenyl-chromen-4-one as white solid (0.62 g, 66%); Rf 0.75 cf SM 0.9 ethyl acetate/hexane (75/25).
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14]1([C:20]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:23]=[C:22](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]12([NH:11][C:12](=[O:13])[NH:11][CH2:1][CH2:2][CH2:3][C:22]3[CH:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:24]([C:25]4[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:29][CH:30]=4)[N:23]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)NC34CC5CC(CC(C5)C3)C4)cc2-c2ccccc2)cc1
Yield: 84 %

Procedure:
The titled compound was prepared in 84% yield from 1-adamantyl isocyanate using the procedure detailed for compound 7. mp 139.4-143.5° C. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J=9 Hz, 2H), 7.37-7.28 (m, 5H), 7.21-7.15 (m, 2H), 6.36 (s, 1H), 5.70-5.64 (m, 2H), 4.68-4.60 (m, 1H), 4.29 (s, 1H), 3.23 (q, J=7 Hz, 2H), 2.78 (t, J=7, 2H), 2.08-1.87 (m, 9H), 1.67-1.59 (m, 6H), 1.29-1.22 (m, 2H). MS (ESI) m/z: 534.25 (M+H+).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12.[OH-].[Na+].CI.[CH3:17]C(O)=O>O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:17])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12
Reactant: CC(=O)O
Reactant: Cc1n[nH]c2nc(S)nc(O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc(O)c2c(C)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-hydroxy-6-mercapto-3-methylpyrazolo[3,4-d]pyrimidine (A-1) (2.86 g, 11.8 mmol) and NaOH (0.8 g, 20 mmol) in water (20 mL) at 5° C., was added CH3I (2.0 g, 14.2 mmol). After stirred at ambient temperature for 30 min, the solution was acidified with HOAc to give the crude product of the title compound (A-2), which used in next step without further purification. MS-ESI (m/z): 197.0 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[ClH:14]>O.S>[Cl:14][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cl
Reactant: Nc1cccnc1CO
Agent: O=N[O-]
Agent: S
Agent: [Na+]
Solvent: O
Product: OCc1ncccc1Cl

Procedure:
A solution sodium nitrite (2.38 g) in water (10 ml) was added dropwise to a stirred mixture of 3-amino-2-hydroxymethylpyridine (4.8 g) in aqueous hydrochloric acid (48% 10 ml) and water (5 ml) at 0°-5° C. This solution of the diazonium salt was added to a hot solution of cuprous chloride (2.5 g) in conc. hydrochloric acid and following cessation of nitrogen evolution the mixture was heated on the steam bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. Filtration, concentration to low bulk and extraction with chloroform yielded 3-chloro-2-hydroxymethylpyridine (3.7 g), m.p. 42°-44° (from n-pentane). This was dissolved in aqueous hydrobromic acid (48% 50 ml), cysteamine hydrochloride (3.22 g) added and the solution obtained was heated under reflux for 6 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded 2-[(2-aminoethyl)-thiomethyl]-3-chloropyridine dihydrobromide (6.0 g), m.p. 250°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and methoxy-acetyl chloride the title compound is obtained as colorless solid.