Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][CH2:11][C:12](=O)[CH2:13]Cl>COCCOC>[Cl:10][CH2:11][C:12]1[N:1]=[C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]2[CH:13]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Product: Cc1cc(C)n2cc(CCl)nc2n1
Temperature: 25 °C

Procedure:
A solution of 2-amino-4,6-dimethylpyrimidine (2.46 g, 20.0 mmol) and 1,3-dichloro-2-propanone (2.67 g, 21.0 mmol) in 1,2-dimethoxyethane (20 mL) was stirred at 45° C. overnight. A precipitate formed, and this was collected by filtration, and was then refluxed with ethanol (15 mL) for 2 hours. After cooling to room temperature, the product precipitated as white needles which were collected by filtration and vacuum dried to yield the title compound pure as its hydrochloride salt (883 mg, 19%). 1H NMR (500 MHz, DMSO-d6): δ7.84 (s, 1H), 6.88 (s, 1H), 4.84 (s, 2H), 2.60 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (732 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (629 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 133–134° C.
Reaction SMILES: [CH3:1][C:2](=O)[C@@H]1[C@]2(C)[C@H]([C@H]3C(=CC2)[C@]2(C)C(=CC(=O)C=C2)CC3)CC1.CS(O)(=O)=O.[CH3:29][C@@H:30]1[CH2:71][C@@H:70]2[C@:57]([CH3:74])([CH2:58][CH:59]=[C:60]3[C@H:69]2[CH2:68][CH2:67][C:66]2[C@:61]3([CH3:73])[CH:62]=[CH:63][C:64](=[O:72])[CH:65]=2)[C@H:31]1[C:32](=[O:56])[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=C(N3CCCC3)N=[C:42]([N:51]3[CH2:55][CH2:54]CC3)[N:41]=2)[CH2:36][CH2:35]1.CS(O)(=O)=O.CS(O)(=O)=O.C[C@@H]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1.Cl.C[C@@H]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1>>[CH2:55]([NH:51][C:42]1[N:41]=[C:40]([N:37]2[CH2:36][CH2:35][N:34]([CH2:33][C:32](=[O:56])[C@@H:31]3[C@:57]4([CH3:74])[C@H:70]([C@H:69]5[C:60](=[CH:59][CH2:58]4)[C@:61]4([CH3:73])[C:66](=[CH:65][C:64](=[O:72])[CH:63]=[CH:62]4)[CH2:67][CH2:68]5)[CH2:71][C@H:30]3[CH3:29])[CH2:39][CH2:38]2)[CH:45]=[CH:2][CH:1]=1)[CH3:54]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C
Agent: CS(=O)(=O)O
Agent: Cl
Product: CCNc1cccc(N2CCN(CC(=O)[C@H]3[C@H](C)C[C@H]4[C@@H]5CCC6=CC(=O)C=C[C@]6(C)C5=CC[C@@]43C)CC2)n1

Procedure:
The preferred amino substituted steroid (XI) is 16α-methyl-21-[4]2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione. More preferred is 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna1,4,9(11)-triene -3,20-dione monomethanesulfonate, 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna1,4,9(11)-triene-3,20-dione bismethanesulfonate and 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione hydrochloride. Most preferred is 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[O:5].[OH-].[K+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23]>O.CC(C)=O>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[O:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4](=[O:5])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccc(C(=O)c2ccccc2O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=S)Oc1ccccc1C(=O)c1ccc(C#N)cc1
Temperature: 50 °C
Yield: 83.4 %

Procedure:
15 g (0.0672 mol) of the 4-(2-hydroxybenzoyl)benzonitrile obtained in Preparation IVb are suspended in a mixture of 150 cm3 of water and 100 cm3 of acetone, 4.15 g (0.0735 mol) of potassium hydroxide are then added and the resulting reaction mixture is stirred and heated for 20 minutes at 50° C. (a red coloration appears, followed by complete dissolution). The solution obtained is cooled to 0° C., a solution of 9.14 g (0.074 mol) of dimethylthiocarbamoyl chloride in 80 ml of acetone is added and the resulting mixture is stirred at room temperature for 3 hours. The reaction medium is hydrolyzed. The precipitate formed is filtered off and then triturated in ether. 17.4 g of the expected product are obtained in the form of a beige solid (yield: 84%).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([CH:24]=1)[C:17]([NH:19][CH2:20][CH2:21][NH:22][OH:23])=[O:18]>N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([CH:24]=1)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH:8]=[O:10])[OH:23])=[O:18]
Reactant: O=C(NCCNO)c1cc(Br)ccc1Cl
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=CN(O)CCNC(=O)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of acetic anhydride (2 mL) and formic acid (1 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride (0.5 mL) was added to a solution of 5-bromo-2-chloro-N-(2-hydroxyamino-ethyl)-benzamide (0.7 g, 2.4 mmol) in pyridine (6 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 1 h and the pyridine removed in vacuo. The residue was chased twice with water and twice with MeOH. The resulting solid was washed with ether/acetonitrile (9:1) to provide the title compound (0.42 g, 55%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.58 (m, 2H); 7.38 (m, 1H); 3.78 (m, 1H); 3.73 (m, 1H); 3.62 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=321.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH:12]1[N:20]2[C:15]([CH2:16][S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=32)=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:13]=1>CN(C=O)C.C(Cl)Cl.[Pd]>[C:2]1([C:12]2[N:20]3[C:15]([CH2:16][S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=43)=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CSc1ccccc1-2
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccccc2)n2c1CSc1ccccc1-2
Temperature: 140 °C
Yield: 31 %

Procedure:
Iodo benzene (0.15 mL, 1.15 mmol, 2 eq), palladium (Il) acetate (6.4 mg, 0.03 mmol, 0.05 eq), and Cul (0.22 g, 1.15 mmol, 2 eq) are taken in pressure tube to which is added ethyl 4H-imidazo[5,1-c][1,4]benzothiazine-3-carboxylate (0.15 g, 0.576 mmol, 1 eq) taken in degassed DMF (6 mL) and the contents are heated at 140° C. for 12 h. The reaction mixture is diluted with DCM and filtered through celite. The filtrate is concentrated, passed through a plug of silica gel and concentrated to get the crude product 60 mg which is taken as such to next step. MS (ESI+): 337.2.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2ncc(OCCN3CCC(N)CC3)nc2c1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (60 mg, 0.26 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine (80 mg, 0.26 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by 1-hydroxybenzotriazole (38 mg, 0.29 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol, 1.15 eq) and N,N-diisopropylethylamine (100 μL, 0.58 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as an off-white solid (18 mg, 13% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:21]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])[CH2:20][CH2:19][O:18][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: CC#N
Product: COCCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Yield: 25.7 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.19 ml (2.22 mmol) 2-methoxyethylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 300 mg (23%) of the title compound as a light brown oil. MS m/e (%): 526 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:21])([F:20])[F:1])=[CH:10][CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(-c3ccccc3C(F)(F)F)ccc12
Product: FC(F)(F)c1ccccc1-c1ccc2c(Cl)ncnc2c1

Procedure:
Reflux a solution of 7-(2-Trifluoromethyl-phenyl)-3H-quinazolin-4-one (1.12 g, 0.0039 mol) in POCl3 for 16 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between saturated aqueous NaHCO3 and EtOAc. Wash the EtOAc layer once with additional NaHCO3, dry it (Na2SO4), and concentrate under reduced pressure to obtain the crude product as a solid. Filter the residue through a 2 inch pad of silica gel (50% EtOAc/Hexanes) and concentrate under reduce pressure to give 4-chloro-7-(2-trifluoromethyl-phenyl)-quinazoline as a pale yellow-brown solid.
Reaction SMILES: C([C:3](CC)(C([O-])=O)[C:4]([O-])=[O:5])C.[Na].[O:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[CH:20][C:21](=[O:23])[CH3:22])[CH2:15][CH2:14]1>C(O)C>[O:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:3][C:4](=[O:5])[CH2:22][C:21](=[O:23])[CH2:20]2)[CH2:15][CH2:14]1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CC(=O)C=CC1CCOCC1
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)CC(C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Diethylmalonate (8.86 ml, 58 mmol) is added dropwise over 3 minutes to a chilled (ice-bath) solution of sodium (1.48 g, 64 mmol) in ethanol (80 ml). Once the addition is complete the cooling bath is removed and reaction is stirred for 25 minutes at room temperature, then the reaction mixture is cooled again in an ice-bath. A solution of 4-(tetrahydropyran-4-yl)-3-buten-2-one (7.50 g, 49 mmol) in ethanol (45 ml) is added to the reaction mixture via a dropping funnel over 15 minutes. Once the addition is complete, the cooling bath is removed and the yellow solution is stirred at room temperature for 19 hours. The reaction mixture is acidified to pH 3 by dropwise addition of 2M aqueous hydrochloric acid, water added to dissolve the precipitate and the reaction mixture is extracted into dichloromethane. The organic extracts are dried over anhydrous magnesium sulphate, filtered and the filtrate concentrated in vacuo. The residue is taken up in isopropanol (50 ml) and a 2M aqueous solution of sodium hydroxide (140 ml) added. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is concentrated in vacuo to remove isopropanol, then heated to 70° C. A solution of 2M aqueous hydrochloric acid is added carefully until the reaction mixture reaches pH 2. The reaction mixture is heated for 2½ hours at 75° C., then cooled to room temperature and the product is extracted into ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and the filtrate concentrated in vacuo to give 5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3].Br.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=1>>[CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=3)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(C)(C)C
Agent: Br
Product: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)(C)C
Yield: 79 %

Procedure:
tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-carbamic acid allyl ester was coupled with 4-(2-amino-ethyl)-2-chloro-phenol hydrobromide salt (intermediate 71) following procedure F to give the title product in 79% yield. LC-MS showed the product had the expected M+H+ of 495. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.3 (d, 1H).) 7.9 (m, 2H) 7.4 (m, 1H) 7.3 (m, 1H) 7.2 (s, 1H) 7.0 (d, 1H) 6.9 (m, 2H) 5.9 (m, 1H) 5.2 (m, 2H) 5.1 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 3.7 (m, 2H) 2.9 (m, 2H) 1.41 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH2:25].Cl.[OH-].[Na+]>O.C(O)C>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1ccc(-c2nc(Cl)cc(C(F)(F)F)n2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccc(C(F)(F)F)nc3)n2)c1
Yield: 4.4 %

Procedure:
A mixture of crude 4-chloro-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine (50 mg, 0.152 mmol), 2-chloro-5-methoxyaniline (50 mg, 0.229 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 120 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×20 ml), with aqueous saturated NaCl (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by preparative TLC to give a white solid (3 mg, 4%). 1H NMR (CDCl3): 9.72 (s, 1H), 8.90 (dd, J=3.0, 7.8 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.75 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.36 (s, 1H), 6.99 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:12]=O)[NH:6]2.[CH2:14]([O:16][C:17]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:18])[CH3:15]>C1COCC1>[CH2:14]([O:16][C:17](=[O:18])[CH:19]=[CH:12][C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([Br:1])[CH:10]=[C:9]([F:11])[CH:8]=2)[CH3:15]
Reactant: O=Cc1cc2c(Br)cc(F)cc2[nH]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cc2c(Br)cc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indole-2-carbaldehyde (1.8 g, 7.4 mmol) in THF (100 mL) at r.t. was added (ethoxycarbonylmethylene)triphenylphosphorane (5 g, 14 mmol). The mixture was stirred for 2 hours at r.t. and the mixture was filtered through a silica gel pad eluted with 40% EtOAc and the filtrate was concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc to give 1.6 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[NH2:19]>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
4-Chloro-6-nitro-quinazoline 4b crude product (6.06 g, 28.90 mmol) was dissolved in 100 mL of isopropanol, followed by addition of 3-chloro-4-(2-pyridylmethoxy)aniline 4c (7.47 g, 31.8 mmol). The reaction mixture was heated to reflux for 5 hours. The mixture was cooled to room temperature, the solid was precipitated, filtered and the filter cake was washed with ethyl acetate, saturated brine (50 mL) and water (150 mL) successively, dried under vacuum to obtain the title compound N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-6-nitro-quinazolin-4-amine 4d (8.38 g, yield 74.8%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])[N:20]4[N:19]=3)[CH:15]=2)[CH2:10][CH:9]1[OH:35])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])[N:20]4[N:19]=3)[CH:15]=2)[CH2:10][CH:9]1[OH:35]
Reactant: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)C(NC(=O)OC(C)(C)C)C(O)C4)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)C(N)C(O)C4)nn12

Procedure:
The titled compound was prepared through an acid catalyzed deprotection using {2-hydroxy-6-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-indan-1-yl}-carbamic acid tert-butyl ester and trifluoroacetic acid in methylene chloride to provide 1-amino-6-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-indan-2-ol; compound with trifluoroacetic acid as a tan lyophilate. LCMS (E/I+) 371 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.97 (s, 1H), 8.33 (m, 3H), 7.86 (d, 2H, J=7.6 Hz), 7.56 (s, 1H), 7.44 (t, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.13 (m, 2H), 6.98 (d, 1H, J=4.5 Hz), 6.94 (d, 1H, J=4.5 Hz), 5.55 (broad s, 1H), 4.31 (d, 2H, J=23 Hz), 3.79 (s, 3H), 3.22 (dd, 1H, J=5.8, 15.4 Hz), 2.71 (dd, 1H, J=4.5, 15.7 Hz).
Reaction SMILES: [C-]#N.[K+].CC(C)(O)[C:6]#[N:7].[Cl:10][C:11]1[CH:12]=[C:13](/[C:18](/[C:37]([F:40])([F:39])[F:38])=[CH:19]\[C:20]([C:22]2[CH:35]=[CH:34][C:25]([C:26]([NH:28][C:29]3([CH3:33])[CH2:32][S:31][CH2:30]3)=[O:27])=[C:24]([CH3:36])[CH:23]=2)=[O:21])[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>C1(C)C=CC=CC=1>[C:6]([C@@:18]([C:13]1[CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]([Cl:10])[CH:12]=1)([C:37]([F:40])([F:39])[F:38])[CH2:19][C:20]([C:22]1[CH:35]=[CH:34][C:25]([C:26]([NH:28][C:29]2([CH3:33])[CH2:32][S:31][CH2:30]2)=[O:27])=[C:24]([CH3:36])[CH:23]=1)=[O:21])#[N:7]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1(C)CSC1
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1(C)CSC1
Temperature: 90 °C
Reaction time: 144 h
Yield: 23.7 %

Procedure:
Potassium cyanide (0.0090 g, 0.139 mmol) and acetone cyanohydrin (0.034 ml, 0.372 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.0600 g, 0.123 mmol) in toluene (3.0 ml). To this vigorously stirred suspension was added 2,3,4,5,6-pentafluorophenyl-methyl quininium chloride (0.0180 g, 0.031 mmol). The reaction mixture was stirred at 90° C. for 6 days. After this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.015 g, 24%) as a light yellow solid. Chiral HPLC analysis (Chiralpack IB, Heptane:2-propanol=70:30, 1 ml/min, retention time 5.91 minutes (major enantiomer), 5.31 minutes (minor enantiomer) indicated that the reaction proceeded with 69% enantioselectivity.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12](O)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([Cl:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2c1CCN(Cc1ccccc1)C2

Procedure:
7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-4-ol (0.1 g, 0.417 mmol) in 3 ml of POCl3 was refluxed for 40 minutes. LCMS indicated complete coversion to the desired product. The excess POCl3 was removed under reduced pressure and taken on to the next step without further purification.