Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.[CH3:13][C@H:14]1[CH2:19][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:17][C@@H:16]([CH3:31])[N:15]1[S:32]([C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][CH:38]([C:44]([NH2:46])=O)[CH2:39]2)(=[O:34])=[O:33]>ClC(Cl)C>[CH3:13][C@H:14]1[CH2:19][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:28])[F:30])=[CH:22][CH:21]=2)[CH2:17][C@@H:16]([CH3:31])[N:15]1[S:32]([C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][CH:38]([C:44]#[N:46])[CH2:39]2)(=[O:34])=[O:33]
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C(N)=O)C2
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C#N)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.4 %

Procedure:
Triethylamine (200 μL, 1.4349 mmol) and phosphorus oxychloride (74 μL, 0.7939 mmol) were added to a solution of 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid amide (254 mg, 0.5105 mmol) in dichloroethane (3 mL). The reaction was stirred for 4 h at room temperature then directly purified by silica gel column chromatography (0-50% EtOAc in hexanes) to afford 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carbonitrile (23 mg, 9%). 1H NMR (400 MHz, CD3OD) δ ppm 7.77 (d, 1H), 7.54 (d, 1H), 7.42 (t, 1H), 7.10 (d, 2H), 6.93 (d, 2H), 4.20-4.00 (m, 2H), 3.65-3.60 (m, 1H), 3.60-3.40 (m, 2H), 3.40-3.20 (m, 4H), 2.80-2.60 (m, 2H), 1.50 (d, 6H). LCMS: 480.0 (M+1)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH:12]1[C:24]2[NH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu](I)I.C1OCCOCCOCCOCCOCCOC1.C1(C)C=CC=CC=1.CN1CCCN(C)C1=O>[C:2]1([N:23]2[C:24]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc2ccccc12
Agent: I[Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CN1CCCN(C)C1=O
Product: c1ccc2c(-n3c4ccccc4c4ccccc43)cccc2c1
Temperature: 170 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
21 g (0.1 mol) of 1-bromonaphthalene, 17 g (0.1 mol) of carbazole, 950 mg (5 mmol) of copper iodide (1), 33 g (240 mmol) of potassium carbonate, and 660 mg (2.5 mmol) of 18-crown-6-ether were put into a 500 mL three-neck flask, and nitrogen substitution was carried out in the flask. To this mixture was added 80 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (abbreviation: DMPU), which was followed by stirring for 6 hours at 170° C. under nitrogen. To this reaction mixture was further added 10 g (50 mmol) of 1-bromonaphthalene, 2.0 g (10 mmol) of copper iodide (I), and 2.6 g (10 mmol) of 18-crown-6-ether, and stirring was further conducted for 7.5 hours at 170° C. Furthermore, to this reaction mixture was added 10 g (50 mmol) of 1-bromonaphthalene, and additional stirring was carried out for 6 hours at 180° C. After the reaction was completed, to this reaction mixture was added about 200 mL of toluene and about 100 of 1 mol/L hydrochloric acid, and then the mixture was filtered through celite. The obtained filtrate was filtered through Florisil and celite. The obtained filtrate was separated into an organic layer and an aqueous layer, and after this organic layer was washed with 1 mol/L hydrochloric acid and then with water, the organic layer was dried over magnesium sulfate. This suspension was filtered through Florisil and celite. The filtrate was concentrated to give an oily substrate, and methanol was added to this oily substrate, followed by irradiation with ultrasound to precipitate a solid. The solid precipitated was collected by suction filtration, giving 22 g of 9-(1-naphthyl)carbazole as white powder (75% yield). The Rf values (SiO2, eluent; hexane:ethyl acetate=10:1) of 9-(1-naphthyl)carbazole, 1-bromonaphthalene, and carbazole were 0.61, 0.74, and 0.24, respectively.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][O:12][CH2:11][C@@H:10]1CS([O-])(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:19]([C@@H:10]1[CH2:11][O:12][CH2:13][C@@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1COC[C@@H]1CS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1COC[C@H]1N=[N+]=[N-]
Temperature: 60 °C
Yield: 52.9 %

Procedure:
[(3S,4S)-4-(Tert-butyl(dimethyl)silyl)oxytetrahydrofuran-3-yl]methanesulfonate (3.00 g, 10.1 mmol) is dissolved in DMF (50 mL). Sodium azide (1.32 g, 20.2 mmol) is added and the reaction is heated to 60° C. for 72 h. Tetra-n-butylammonium iodide (0.400 g, 1.08 mmol) is added and the temperature is raised to 120° C. for 14 days. Water is added and the product is extracted into EtOAc. The organic layer is washed with water a second time and then dried over magnesium sulfate, filtered, and concentrated to give 2.9 g of crude product as a pale yellow oil. The crude product is purified on silica gel (120 g, 2-20% EtOAc/hexanes, observed on TLC with KMnO4 staining) to give the title compound as a colorless oil (1.3 g, 53%). GC-MS m/z 186 (M-tBu)+.
Reaction SMILES: N1CCCC1COC1C=C2C(C(N)=CC=N2)=NC=1.[F:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:33]([CH2:36][NH:37][C:38]4[CH:39]=[CH:40][N:41]=[C:42]5[C:47]=4[N:46]=[CH:45][C:44]([O:48][CH2:49][C@H:50]4[CH2:54][CH2:53][CH2:52][N:51]4C(OC(C)(C)C)=O)=[CH:43]5)=[N:34][N:35]=3)[N:32]=2)[CH:23]=[C:24]([F:26])[CH:25]=1.COC1C=C2C(C(OCC3N4N=C(C5C=NC(N6CCNCC6)=CC=5)C=CC4=NN=3)=CC=N2)=CC=1>>[F:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:33]([CH2:36][NH:37][C:38]4[C:47]5[C:42](=[CH:43][C:44]([O:48][CH2:49][C@H:50]6[CH2:54][CH2:53][CH2:52][NH:51]6)=[CH:45][N:46]=5)[N:41]=[CH:40][CH:39]=4)=[N:34][N:35]=3)[N:32]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc2c(NCc3nnc4ccc(-c5cc(F)cc(F)c5)nn34)ccnc2c1
Agent: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N6CCNCC6)nc5)nn34)ccnc2c1
Agent: Nc1ccnc2cc(OCC3CCCN3)cnc12
Product: Fc1cc(F)cc(-c2ccc3nnc(CNc4ccnc5cc(OC[C@H]6CCCN6)cnc45)n3n2)c1

Procedure:
(R)—N-(6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine. The title compound was prepared from (R)-tert-butyl 2-((8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate following the procedure used to make 7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline. m/z: 489 (M+H). Calc'd. for C25H22F2N8O—488.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18]C)=[O:17])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2cccc(-c3ccccc3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(-c2cccc(-c3ccccc3)n2)c1

Procedure:
Part C. Methyl 3-(6-phenyl-pyridin-2-yl)-benzoate is saponified using sodium hydroxide, and workup afforded the acid title product. MS (ES+): m/e 276 (100).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[N+:22]([O-])=O)[C:13]1=[O:25])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C(O)C>[Pd]>[C:9]([O:8][CH2:7][CH:6]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[NH2:22])[C:13]1=[O:25])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(COC(C)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCC(COC(C)=O)n1ccc2c(N)cccc2c1=O

Procedure:
2-(5-Nitro-1-oxoisoquinolin-2(1H)-yl)propane-1,3-diyl diacetate (6.3 g, 0.018 mol) was stirred with palladium 10% wt. on calcium carbonate (0.6 g, 0.003 mol) in ethanol (100 mL, 2 mol) under hydrogen (balloon) over 1 h at room temperature. The catalyst was filtered, the filtrate was concentrated to dryness to give a yellow oil. MS m/z (M+H) 319.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2ncn[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1ncnc1-c1cccc(Br)c1
Yield: 11.1 %

Procedure:
This reaction was carried out as described in Example 40, step c, using 5-(3-bromophenyl)-1H-[1,2,4]triazole (1.60 g, 7.2 mmol), K2CO3 (2.47 g, 17.8 mmol) and MeI (667 μl, 10.7 mmol). The residue was purified by column chromatography (silica gel, 80% Et2O/isohexane) to yield first 5-(3-bromophenyl)-1-methyl-1H-[1,2,4]triazole (190 mg, 11%), and then the solvent polarity was increased to 100% EtOAc to yield 3-(3-bromophenyl)-1-methyl-1H-[1,2,4]triazole (935 mg, 55%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])=[CH:7][C:6]=1[C:17]([F:20])([F:19])[F:18])(=[O:4])=[O:3].C(O)(=[O:23])C>[Fe]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:23])[CH3:13])=[CH:7][C:6]=1[C:17]([F:20])([F:19])[F:18])(=[O:4])=[O:3]
Reactant: CC(=O)O
Reactant: CC(=Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1)[N+](=O)[O-]
Agent: [Fe]
Product: CC(=O)Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of freshly prepared 1-methanesulfonyl-4-(2-nitro-propenyl)-2-trifluoromethyl-benzene (59b) (14 g, 45 mmol) in acetic acid (100 ml) is added slowly to a stirred slurry of Iron powder (27.6 g, 495 mmol) in acetic acid (100 ml) at 60° C. The reaction is then stirred at 100° C. for 2 hours then allowed to cool and poured onto ice-water (300 ml). After filtration through celite, washing with dichloromethane (500 ml), the organic extract is separated and washed with water (3×300 ml) followed by brine (500 ml). The organic extract is dried (MgSO4) and concentrated to give a red oil. Chromatography on silica, eluting with ethyl acetate-hexane, affords the titled compound as a white solid.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[O:36][CH3:37])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:17]2[C:18]3[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:12][C:13]=3[C:14]([O:36][CH3:37])=[CH:15][CH:16]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1NC(=S)NC(=O)c1ccccc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)c2sc(NC(=O)c3ccccc3)nc12
Yield: 58.3 %

Procedure:
To a stirred solution of 500 mg (0.98 mmol) 1-benzoyl-3-{5-[bis-(4-methyl-benzyl)-amino]-2-methoxy-phenyl}-thiourea in 7 ml chloroform was added dropwise 0.050 ml (0.98 mmol) bromine and the reaction mixture heated at reflux for 18 hours. The mixture was then diluted with ethyl acetate and washed with water and then with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane) afforded 290 mg (58%) N-{7-[bis-(4-methyl-benzyl)-amino]-4-methoxy-benzothiazol-2-yl}-benzamide as a yellow solid. ES-MS m/e (%): 394 (M+Na+, 14), 508 (M+H+, 100).
Reaction SMILES: CS[C:3]1[C:9]2=[CH:10][C:11]3[C:16]([N:8]2[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.C1(C)C(C)=[CH:23][CH:24]=[CH:25][CH:26]=1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CCOC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH2:26]([N:4]1[CH2:32][CH2:31][N:8]([C:3]2[C:9]3=[CH:10][C:11]4[C:16]([N:8]3[CH2:7][C:6]3[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=3[N:4]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][CH2:3]1)[CH2:25][CH2:24][CH3:23]
Reactant: CSC1=Nc2ccccc2Cn2c1cc1ccccc12
Reactant: Cc1ccccc1C
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Product: CCCCN1CCN(C2=Nc3ccccc3Cn3c2cc2ccccc23)CC1

Procedure:
A mixture of 7.1 g of 12-methylthio-6H-indolo[2,1-c][1,4]benzodiazepine, the product of Example 1c, 6.64 g of 4-n-butyl-1-piperazine and 20 ml of xylene in a pressure bottle was heated to 240° C. for 3 hours. The reaction mixture was dissolved in EtOAc, washed with water, and dried anhydrous over Na2SO4. The crude product (after removal of solvent) was dissolved in MeOH and treated with one equivalent of fumaric acid to give a solid. Recrystallization of the fumarate salt from DMF yielded the title compound, a colorless solid, mp 197° C. (dec).
Reaction SMILES: C([CH2:5][N:6]1[CH2:10][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[C@H:8]([C:15]([O:17][CH3:18])=[O:16])[CH2:7]1)(OC)=O.[CH3:19]C(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1>[C:11]([CH:9]1[CH:8]2[CH2:7][N:6]([CH2:5][C:15]2([O:16][CH3:19])[O:17][CH3:18])[CH2:10]1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CN1C[C@@H](C(=O)OC)[C@H](C(=O)OC)C1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN2CC1C(OC)(OC)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A solution of 1-carbomethoxymethyl-trans-3,4-dicarbomethoxypyrrolidine (5 g, 19.31 mmol) in toluene (75 ml) was added dropwise over a 1 h period to a rapidly stirred solution of potassium-t-butoxide (9 g, 80 mmol) in toluene (250 ml) at 130° C. The mixture was refluxed for 4 h, cooled to room temperature and concentrated hydrochloric acid (75 ml) added dropwise and stirred for 0.25 h. The organic phase was extracted with further portions of acid (3×50 ml) and the combined aqueous heated at 110° C. for 16 h. The solvent was then removed under vacuum, the residue dried and taken up into methanol (saturated with hydrogen chloride) (150 ml). The mixture was stirred at room temperature for 24 h and the solvent removed under vacuum. The residue was dissolved in water (50 ml), basified to pH >10 with potassium carbonate and extracted with dichloromethane (5×150 ml). The combined extracts were dried (Na2SO4 ) and the residue remaining after removal of solvents was chromatographed through silica-gel using dichloromethane/methanol (93:7) as eluant, to give the title ester as a yellow liquid (0.5 g). An analytical sample was prepared as the hydrogen oxalate salt, mp 134.5°-136.5° C. (isopropylalcohol); (Found: C, 47.04; H, 6.20, N, 4.50. C10H17NO4. (CO2H)2 requires C, 47.21; H, 6.27; N, 4.59%); δ (360 MHz, CDCl3) 2.44 (1H, dd, J=3 and 9.8 Hz, CH of CH2 --N); 2.63 (1H, dd, J=3 and 12.7 Hz, CH of CH2 --N); 2.77 (1H, d, J=12.7 Hz, CH of CH2 --N); 2.80-3.10 (5H, m, 2 of CH and 1.5 of CH2); 3.11 (3H, s, OMe); 3.24 (3H, s, OMe); 3.71 (3H, s, CO2Me).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:9]=[C:8](F)[CH:7]=2)#[N:2].CO.C[C:26](C)([O-:28])C.[K+].Cl>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:9]=[C:8]([O:28][CH3:26])[CH:7]=2)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: CN1CCC(Oc2cc(F)cc3ncc(C#N)c(O)c23)CC1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: COc1cc(OC2CCN(C)CC2)c2c(O)c(C#N)cnc2c1
Temperature: 70 °C
Yield: 73 %

Procedure:
A mixture of 3-cyano-7-fluoro-4-hydroxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (600 mg), methanol (0.40 ml) and potassium tert-butoxide (1.0M solution in tetrahydrofuran; 10.0 ml) in anhydrous dimethyl sulphoxide (20 ml) was heated at 70° C. for 16 hours. The solution was cooled and then diluted with water (100 ml). Dilute hydrochloric acid was added until pH6 was reached and the by-product precipitate (3-cyano-4-hydroxy-5,7-dimethoxyquinoline) was filtered off. The filtrate was pumped onto a cation exchange cartridge (Waters Oasis MCX 6.0 g) and washed on with water. The column was flushed successively with water (200 ml), methanol/water (1:1; 200 ml) and methanol (200 ml). The product was eluted off the column with methanol containing triethylamine (1%). The fractions containing the product were combined and evaporated. This gave the title compound as an white solid (460 mg, 73%); NMR spectrum: (DMSOd6) 1.67 (m, 2H), 1.83 (m, 2H), 2.12 (m, 2H), 2.15 (s, 3H), 2.64 (m, 2H), 4.31 (m, 1H), 6.31 (d, 1H), 6.56 (d, 1H), 8.16 (s, 1H); Mass spectrum: M+H+ 314.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH2:12]1[S:16](=[O:18])(=[O:17])[O:15][CH2:14][CH2:13]1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][CH2:13][CH2:12][S:16]([OH:18])(=[O:17])=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: Fc1ccc2c(c1)CCCN2
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCCc2cc(F)ccc21
Temperature: 150 °C

Procedure:
To 6,05 g (40 mMol) 6-fluoro-1,2,3,4-tetrahydroquinoline in 20 ml acetone, 5.9 g (48 mMol) of propane sultone dissolved in 20 ml acetone are added dropwise for a period of 40 minutes at 50° to 60° C. After 24 hours of refluxing and again after 48 hours a further 5.9 g of propane sultone are added. After a total of 60 hours of refluxing, the reaction mixture is concentrated by evaporation and the volatile components are removed in high vacuum (0.01 torr) by heating to about 150° C. The residue is recrystallized from 115 ml methanol.
Reaction SMILES: [OH:1][C:2]1C=C(C(O)=O)C(N)=C[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=[O:23].C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C=O)C>[C:2]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=[O:23])(=[O:1])[CH3:3]
Reactant: O=c1[nH]cnc2ccc(O)cc12
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2nc[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Using an analogous procedure to that described in the portion of Example 1 which is concerned with the preparation of starting materials, 5-hydroxyanthranilic acid was converted into 6-hydroxyquinazolin-4-one. Acetic anhydride (1.38 g) was added dropwise to a mixture of 6-hydroxyquinazolin-4-one (2 g), triethylamine (1.37 g) and DMF (60 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 6-acetoxyquinazolin-4-one which was reacted with thionyl chloride using an analogous procedure to that described in the portion of Example 1 which is concerned with the preparation of starting materials.
Reaction SMILES: [C:1]([C:3]([NH:9][C:10]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH:24]2[CH2:26][CH2:25]2)=[CH:14][N:13]=1)=[O:11])([CH3:8])[CH2:4][CH:5]1[CH2:7][CH2:6]1)#[N:2].[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+].N([O-])=O.[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH:24]1([C:15]2[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:17][C:12]([C:10]([NH:9][C:3]([CH3:8])([C:1]3[N:29]=[N:30][NH:31][N:2]=3)[CH2:4][CH:5]3[CH2:6][CH2:7]3)=[O:11])=[N:13][CH:14]=2)[CH2:25][CH2:26]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C#N)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1nn[nH]n1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 71.3 %

Procedure:
To a solution of N-(1-cyano-2-cyclopropyl-1-methyl-ethyl)-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 150a, 300 mg, 817 μmol) in DMF (4 ml) under an argon atmosphere was added ammonium chloride (218 mg, 4.08 mmol), sodium azide (265 mg, 4.08 mmol). The reaction mixture was stirred at 120° C. under microwave radiation for 45 minutes. After cooling, the reaction mixture was poured into a mixture of ice water (12 mL) and ethyl acetate (4 mL). To the bi-phasic mixture was added sodium nitrite (231 mg, 3.35 mmol) (to decompose the excess of sodium azide), followed by a slow addition of a 4M aqueous solution of hydrochloric acid (until pH=2) under ice cooling. The bi-phasic mixture was then stirred at room temperature for 10 minutes, then diluted with more ethyl acetate and poured into a separatory funnel. After extraction the organic phase was collected and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated down to dryness to yield the title compound (239 mg, 71%) as a crude solid which was used without any purification. MS (ESI, m/z): 411.5 (M+H+).
Reaction SMILES: [C@H:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CO[CH:13]=[CH:14][CH:15]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[C@H:1]1([NH:10][CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:21]([O:23][CH3:24])=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC=CC=C(C(=O)OC)C(=O)OC
Reactant: N[C@@H]1CCc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)C(=CC=CN[C@@H]1CCc2ccccc21)C(=O)OC
Temperature: 65 °C
Yield: 97.4 %

Procedure:
A 500 ml round-bottom flask was charged with 5.0 g (1.0 eq.) (R)-2,3-dihydro-1H-inden-1-amine and 7.5 g (1.0 eq.) dimethyl 2-(3-methoxyallylidene)malonate in 120 ml dry THF. The mixture was heated at 65° C. under N2 for 3 hrs. Then the solvent was removed in vacuo, and the crude mixture was purified by silica gel flash column chromatography to afford (R)-dimethyl 2-(3-(2,3-dihydro-1H-inden-1-ylamino)allylidene)malonate as a yellow solid (11.0 g) in 97% yield.
Reaction SMILES: [CH3:1]C1CCC[C@@]2(CO)C=1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@H]2O.[C:23]([O:27][C@H:28]1[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:49]([CH2:50][CH2:51][C@:29]12[CH3:30])[C@:42]1([CH2:43][O:44][C:45](=[O:48])[CH2:46][CH3:47])[C:37](=[CH:38][CH2:39][CH2:40][C@@H:41]1C)[CH2:36][CH2:35]3)(=[O:26])[CH2:24][CH3:25]>>[C:23]([O:27][C@H:28]1[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:49]([CH2:50][CH2:51][C@:29]12[CH3:30])[C@:42]1([CH2:43][O:44][C:45](=[O:48])[CH2:46][CH3:47])[C:37](=[C:38]([CH3:1])[CH2:39][CH2:40][CH2:41]1)[CH2:36][CH2:35]3)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)OC[C@@]12C(=CCC[C@@H]1C)CC[C@H]1[C@@H]3CC[C@H](OC(=O)CC)[C@@]3(C)CC[C@@H]12
Reactant: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CCC1
Product: CCC(=O)OC[C@]12CCCC(C)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CC)CC[C@@H]12

Procedure:
Substituting 1α,17α-dimethyl-4-androstene-17β,19-diol and 4-methyl-4-androstene-17β,19-diol for the 1α-methyl-4-androstene-17β,19-diol above results in the preparation of 1α,17α-dimethyl-4-androstene-17β,19-diol dipropionate and 4-methyl-4-androstene-17β,19-diol dipropionate.