Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])(=[O:7])[NH2:6]>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:12]([O:3][CH2:2][CH2:1][O:4][C:12](=[O:13])/[CH:11]=[CH:10]\[C:9](=[O:14])[NH:8][C:5](=[O:7])[NH2:6])(=[O:13])/[CH:11]=[CH:10]\[C:9](=[O:14])[NH:8][C:5](=[O:7])[NH2:6]
Reactant: OCCO
Reactant: NC(=O)N1C(=O)C=CC1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: NC(=O)NC(=O)/C=C\C(=O)OCCOC(=O)/C=C\C(=O)NC(N)=O
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A mixture of 3 g of ethylene glycol (0.048 moles), 12 g of N-carbamylmaleimide (0.086 moles) and 0.3 g of zinc chloride (0.0022 moles) in 70 mL of acetonitrile was heated to reflux. After 3 hours, a lot of solid material had been produced from the mixture. The mixture was filtered and the solids washed with acetonitrile and dried to afford 11.7 g of ethylene glycol bismaleurate. M.P.: 158°-60° C.; 1H NMR (DMSO-d6): δ 10.5 (s, 2 H), 7.2-7.8 (m, 4 H), 6.2-6.4 (m, 4 H), 4.3 (s, 4 H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O.CO>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:5]4[CH2:6][CH2:7][CH:3]([N:2]([CH3:8])[CH3:1])[CH2:4]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: CN(C)C1CCNC1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCC(N(C)C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
N,N-dimethylpyrrolidin-3-amine (114 mg, 1.00 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (136 mg, 0.35 mmol) in anhydrous dimethylsulfoxide (1.75 ml) at 25° C. The resulting solution was stirred at room temperature for 20 mins. The reaction mixture was diluted with methanol (5.00 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product as a brown oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (130 mg, 80%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44]OS(C)(=O)=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:50]1[CH2:54][CH2:53][NH:52][C:51]1=[O:55]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:20]([CH2:44][N:50]3[CH2:54][CH2:53][NH:52][C:51]3=[O:55])[CH2:21][N:22]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:23][CH:24]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCN1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CC(CN2CCNC2=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 149(f), by reacting tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methanesulphonyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with imidazolidin-2-one there was obtained tert-butyl (3RS,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-(2-oxo-imidazolidin-1-ylmethyl)-piperidine-1-carboxylate as a yellowish oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]([F:19])[CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([NH:22][C:13]([C@@H:12]1[CH2:16][CH:17]([F:19])[CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:15])[CH3:21]
Reactant: CCN
Reactant: O=C(O)[C@@H]1CC(F)CN1C(=O)OCc1ccccc1
Product: CCNC(=O)[C@@H]1CC(F)CN1C(=O)OCc1ccccc1

Procedure:
With 3.02 g of the compound obtained in Step 11-2 and 1.16 g of an aqueous solution of 70% ethyl amine as starting material, 1.92 g of the title compound (colorless solid) was obtained by a similar method to Step 10-1.
Reaction SMILES: C(=O)=O.CC(C)=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1.CC([O-])(C)C.[K+].[CH3:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39]Br>C1COCC1>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH:15]([CH2:36][C:37]3[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=3[CH3:39])[N:16]=[C:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:11]=2[CH:10]=1
Reactant: Cc1ccccc1CBr
Reactant: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(Cc3ccccc3C)C(=O)N(C)c3ccc(Cl)cc32)cc1
Yield: 84.1 %

Procedure:
To a stirred and cooled (dry ice/acetone bath) solution of E1 (0.50 g, 1.59 mmol) in THF (8 mL) was slowly added 1 M KOtBu (2.4 mL, 2.4 mmol, 1.5 eq). The resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min followed by the slow addition of a solution of 2-methylbenzyl bromide (0.46 g, 2.5 mmol, 1.5 eq) in THF (2 mL). After stirring another ˜35 min at −78° C., the reaction mixture was quenched with water and diluted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated (rotovap, then high vacuum). Chromatography over silica gel using 20-40% EtOAc/heptane gave 0.56 g (yield of 84%) of the title product. Noting that, when using benzyl chlorides as alkylating agents, tetrabutyl ammonium iodide was added along with the alkylating agent at the low temperature. 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 3.41 (s, 3H), 3.5-3.65 (m, 2H), 3.74 (dd, 1H), 3.84 (s, 3H), 6.89 (dt, 2H), 7.05-7.15 (m, 3H), 7.25-7.35 (m, 3H), 7.45-7.5 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36]3)[CH:30]=2)[N:25]=1)([CH3:23])[CH2:9][O:10][P:11]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2[C:67]([F:70])([F:69])[F:68])N=1)(C)CO)(C)(C)C>>[C:1]([O:5][C:6](=[O:45])[NH:7][C:8]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:34][C@H:35]3[CH2:36][CH2:37][C@H:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:39][CH2:40]3)[C:30]=2[C:67]([F:70])([F:69])[F:68])[N:25]=1)([CH3:23])[CH2:9][O:10][P:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Product: CC(C)(C)OC(=O)NC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
[1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-2-(di-tert-butoxy-phosphoryloxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester Enantiomer 1 was synthesized as per [1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-2-(di-tert-butoxy-phosphoryloxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester Enantiomer 1 (Example 29) in 68% yield using {1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-2-hydroxy-1-methyl-ethyl}-carbamic acid tert-butyl ester Enantiomer 1 as starting material.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[C:30](Cl)=[O:31])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:37]([C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:35]=1[OH:36])[C:30]([O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:31])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)ON(Cc2ccccc2)Cc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 27.9 g of dibenzylhydroxylamine and 10.3 g of pyridine in 100 ml of methylene chloride is added a solution of 39.0 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride in 100 ml of methylene chloride. After stirring the mixture at room temperature for 24 hours, the reaction mixture is washed with 10% aqueous hydrochloric acid, water, brine and dried. Evaporation followed by crystallization of the residue from heptane affords the title compound as a white solid: mp 90°-92° C.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:46][C:47]1[C:51]([CH3:52])=[N:50][O:49][N:48]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:46][C:47]3[C:51]([CH3:52])=[N:50][O:49][N:48]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nonc1CBr
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1nonc1Cn1nnc2c(N3CC(F)(F)C(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as light-yellow gum. MS (m/e): 415.3 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:23][CH2:24][C:25]2[C:30]([F:31])=[CH:29][C:28]([Br:32])=[CH:27][C:26]=2[F:33])=[N:7][S:8][C:9]=1[NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:12])=O.[NH3:34]>CO.O1CCCC1>[Br:32][C:28]1[CH:29]=[C:30]([F:31])[C:25]([CH2:24][O:23][C:6]2[C:5]([C:3]([NH2:34])=[O:2])=[C:9]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:12])[S:8][N:7]=2)=[C:26]([F:33])[CH:27]=1
Reactant: N
Reactant: COC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1
Temperature: 0 °C
Yield: 76 %

Procedure:
In a 1 Liter autoclave 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 27.0 g) was slurried in methanol (270 mL, 10 volumes) and tetrahydrofuran (270 mL, 10 volumes). The mixture was cooled to 0° C. and stirred at 600 rpm. Anhydrous ammonia gas was charged carefully, keeping the temperature below 10° C. Once a steady pressure of around 10 psi was maintained, the mixture was heated to 40° C. The pressure increased to about 45 psi. The pressure was adjusted to 50 psi and stirred at 600 rpm and 40° C. for 90 hours. The stir rate was then adjusted to 1000 rpm and stirred for an additional 24 hours. The ammonia was removed by vacuum, and the mixture was cooled to 20° C. and transferred out of the reactor. The mixture was filtered to remove insoluble solids (non-product related). The filtrate was diluted with 2-propanol (270 mL, 10 volumes), and the tetrahydrofuran and methanol were distilled atmospherically. Additional 2-propanol (135 mL, 5 volumes) were added, then the mixture was distilled to approximately 250 mL total volume. The slurry was cooled to 20° C. and stirred 18 hours. The solids were filtered and then dried under vacuum to give 19.9 grams of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide (76% yield). 1H NMR (DMSO-d6): δ 10.98 (s, 1H); 8.18 (m, 1H); 7.55 (m, 3H); 6.80 (s, 1H); 5.41 (s, 2H); 3.08 (m, 2H); 2.47 (m, 6H); 1.62 (m, 4H); 1.42 (m, 4H). MS (API-ES pos) 532/534 (M+H)+, base.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=[O:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:31])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29]I)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:19]([O:23][C:24](=[O:31])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[C:16](=[O:18])[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)c1c(O)cccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-benzyloxy-6-hydroxyphenyl)-ethanone (100 mg, 0.41 mmol) and (4-iodobutyl)-carbamic acid tert-butyl ester (Example 123, step A) (150 mg, 0.5 mmol) in DMF (5 mL) is added K2CO3 (113 mg, 0.82 mmol) and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26].CC#N.O.CC#N>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])[C@H:10]([C:15]([CH3:22])([CH3:23])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Solvent: CC#N
Solvent: O
Product: CC(C)CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C

Procedure:
The title compound is prepared as described above for Example 9/step F (Scheme 5) from (3S*,4S*)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and isobutylamine. MS (LC-MS): 401.1 [M+H]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 3.70 min.
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC[O:10][CH2:11][CH3:12])C.P(Cl)(Cl)(Cl)=O.[CH3:18][C@H:19]1[C@@:36]2([CH3:37])[C:23]([CH2:24][C@@H:25](C)[C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][C@@H:29]([F:39])[C:30]2=[O:38])=[CH:22][C:21](=O)[CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:20][C@H:19]1[C@@:36]2([CH3:37])[C:23]([C:22](=[CH2:21])[C@@H:25]([CH3:24])[C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][C@@H:29]([F:39])[C:30]2=[O:38])=[CH:12][C:11](=[O:10])[CH2:18]1
Reactant: C[C@@H]1CC2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Reactant: CCOCOCC
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1β,7α-dimethyl-16α-fluoroandrost-4-ene-3,17-dione (0.896 g, 2.7 mmol) is stirred at reflux for about 5 hrs, i.e. until the starting material has disappeared. The suspension is allowed to cool and under vigorous stirring a saturated sodium carbonate solution is added dropwise until the pH of the aqueous layer becomes alkaline. The organic layer is separated, washed to neutrality with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue is purified by chromatography on silica gel using hexane/ethyl acetate as eluant. Thus the pure 1β,7α-dimethyl-16α-fluoro-6-methylenandrost-4-ene-3,17-dione is obtained in 60% yield (0.56 g).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[N:11][C:10]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:32]([CH3:31])(=[O:34])=[O:33])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: NCCCCC(=O)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCCC(=O)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.9 %

Procedure:
N1-(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta-[d][1,3]thiazol-2-yl)-5-aminopentanamide (115 mg, 0.34 mmole) was dissolved in 2 ml of dry THF, cooled with an ice bath, triethylamine was added (96 μl, 0.69 mmole) followed by addition of 27 μl of methane sulfonyl chloride (0.35 mmole). The reaction mixture was stirred at room temperature for 6 hours, quenched with saturated sodium carbonate solution and extracted with 3×3 ml of ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution, concentrated and chromatographed (12 g of silica gel, EtOAc/hexanes/7N NH3 in MeOH, 50:50:2) to give 53 mg of the desired product as a white solid (38%): m.p. 145-147° C.; 412 (ESMS, MH+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1)=[O:10]>>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: O=C(c1ccc(CBr)cc1)c1cccs1
Agent: [Na+]
Product: N#CCc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5.9 parts of sodium cyanide in 40 parts of dimethyl sufoxide is heated to 60° C and there are added at once 11.3 parts of α-bromo-p-tolyl 2-thienyl ketone (exothermic reaction: temperature rises to 100° C). The whole is stirred for 2 hours at 60° C. After cooling, the reaction mixture is poured onto water and the product is extracted three times with 450 parts of chloroform. The combined extracts are washed twice with 200 parts of water, dried and evaporated. The dark-coloured residual tar is extracted several times with ether. The combined ether extracts are stirred with activated charcoal, filtered and evaporated. The residue is triturated in petroleumether (solid carbon dioxide) and the whole is evaporated, yielding 2-[-p-(2-thenoyl)-phenyl]acetonitrile as a residue.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH2:17][CH2:16]2)[N:3]=1.I[CH2:31][CH:32]1[CH2:35][CH2:34][CH2:33]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[CH2:17][CH2:16]2)[N:3]=1
Reactant: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1O
Reactant: ICC1CCC1
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1OCC1CCC1

Procedure:
The title compound was prepared from 4-amino-6-hydroxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline and iodomethyl cyclobutane [Bailey et al J Org Chem, 60, 297-300 (1995)] following a similar procedure to that described in Example 2(b), and was obtained as a solid (14%). Rf 0.40 (0.880 aqueous ammonia:methanol:dichloromethane 1:7:92, v/v). MS m/z 471 (MH)+. Found: C, 59.35; H, 7.12; N, 17.44; C24H34N6O4 0.15CH2Cl2 0.15 H2O, requires C, 59.68; H, 7.18; N, 17.28%.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=O)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Solvent: CC#N
Product: CCCCc1nc(=O)c2cc(C=CC(=O)OCC)ccc2[nH]1
Yield: 46.4 %

Procedure:
A mixture of 3.202 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde and 5.093 g of (carbethoxymethylene)triphenylphosphorane in 50 ml of acetonitrile is heated at reflux for 18 hours. The reaction mixture is cooled and the resulting solid washed with ether and dried to give 1.94 g of the desired product. CI mass spec 301 (MH+)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.Cl[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]=O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1)([OH:18])=[O:17]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: O=C(O)c1ccccc1Cl
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C(O)c1ccccc1-n1nc(C(=O)O)c2ccccc21
Yield: 30.3 %

Procedure:
3-Indazolecarboxylic acid (4.10 g), 3.90 g of 2-chlorobenzoic acid, 3.90 g of potassium carbonate and 0.18 g of copper(II) oxide were stirred in 150 ml of nitrobenzene at 170° to 180° C. for 3 hours. After cooling, 100 ml of water was added to the reaction mixture, and the insoluble substance was removed by filtration. The resulting solution was washed with chloroform, and the aqueous layer was decolored with active charcoal and then filtered. The filtrate was made acidic with 50 ml of 1N hydrochloric acid and then extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from methanol-chloroform-ether to obtain 2.13 g (30.2%) of 1-(2-carboxyphenyl)-3-indazolecarboxylic acid.