Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C@@H:20]([OH:35])[CH2:21][C@@H:22]([C:31]([OH:34])([CH3:33])[CH3:32])[C:23]([NH:25][CH2:26][C@@H:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[O:44]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]([NH:53][C@H:54](C(O)=O)[CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]=[CH:58][CH:57]=2)=[O:52])[CH2:46][CH2:45]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[O:44]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]([NH:53][C@H:54]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:36][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[C@@H:20]([OH:35])[CH2:21][C@@H:22]([C:31]([OH:34])([CH3:33])[CH3:32])[C:23]([NH:25][CH2:26][C@@H:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]=[CH:58][CH:57]=2)=[O:52])[CH2:46][CH2:45]1
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1cccc2ccccc12)C(=O)O
Reactant: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)CN1CCOCC1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of 150 mg (0.25 mmoles) of (2S, 4S, 5S)-5-{N-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino}-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-[2(S)-methylbutyl]hexanamide (prepared as described in Example 1) in 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and diethyl ether was added to the residue. The solvent was then again removed by distillation under reduced pressure. This operation was repeated in total three times, and then the final residue was dried under vacuum for 8 hours. The dried material was suspended in 10 ml of anhydrous tetrahydrofuran, and then 100 mg (0.29 mmoles) of N-morpholinoacetyl-3-(1-naphthyl)-L-alanine were added to the resulting suspension, followed by 0.04 ml (0.26 mmoles) of 95% diethyl cyanophosphate and 0.11 ml (0.79 mmoles) of triethylamine, all whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel thin layer chromatography (using a 10:1 by volume mixture of methylene chloride and methanol as eluent), to give 150 mg (yield 73%) of the title compound as white crystals, melting at 141°-143° C.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][C:16]1[C:20](B(O)O)=[C:19]([CH3:24])[O:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[Cl:14][C:4]1[CH:3]=[C:2]([C:20]2[C:16]([CH3:15])=[N:17][O:18][C:19]=2[CH3:24])[CH:13]=[CH:12][C:5]=1[NH:6][CH2:7][C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)CNc1ccc(Br)cc1Cl
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1ccc(NCC(F)(F)F)c(Cl)c1
Temperature: 90 °C

Procedure:
A mixture of 4-Bromo-2-chloro-N-(2,2,2-trifluoroethyl)aniline (5280 mg, 18.3 mmol), 3,5-dimethylisoxazole-4-boronic acid, pinacol ester (4082.76 mg, 18.3 mmol), PEPPSI″-IPr catalyst (1247.24 mg, 1.83 mmol), Cesium carbonate (17889.52 mg, 54.91 mmol) in 120 mL DME:H2O (2:1) was heated to 90° C. under argon. The reaction mixture was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with water then brine and dried over sodium sulfate. Purification on silica gel (Hexanes/EtOAc) afforded 2-chloro-4-(3,5-dimethylisoxazol-4-yl)-N-(2,2,2-trifluoroethyl)aniline.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[Cl:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11].[OH2:19]>CO>[Cl:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:19][CH2:6][CH3:7])=[O:11]
Reactant: O
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CO
Product: CCOC(=O)C(Cl)c1ccccc1
Yield: 83.4 %

Procedure:
To a solution of triethylamine (63.5 mmol, 8.7 mL) in methanol there was added dropwise, at 0° C., α-chlorophenylacetyl chloride (53 mmol, 7.6 mL), and the reaction mixture was then stirred over a period of 3.5 h at room temperature. The reaction mixture was then added to 100 mL of water and extracted with EA (3×100 mL). Following the combination of the organic phases, they were dried over MgSO4 and concentrated in vacuo to give 8.76 g (83.4%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:11][CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][C:9]#[N:10])=[O:4].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]([CH2:11][CH:12]=[CH:13][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]#[N:10])=[O:4]
Reactant: C=CCC(CCCC#N)C(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(CC=Cc1cccnc1)CCCC#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 23.5 g of 5-methoxycarbonyl-oct-7-enenitrile, 20.07 g of 3-bromopyridine and 0.79 g of tri-o-tolylphosphine in 200 ml of 2:1 acetonitrile/triethylamine is stirred at room temperature under nitrogen for 0.5 h. Palladium acetate (0.27 g) is added and the mixture is stirred under reflux for 40 h. An additional 0.13 g of palladium acetate is added and the reaction mixture is further heated under reflux for 20 h. The reaction mixture is evaporated to dryness and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with water, and then with 3N hydrochloric acid. The acid extract is washed with ethyl acetate, made basic to pH 8-9 with aqueous ammonia and reextracted with ethyl acetate. The ethyl acetate extract is dried and evaporated to dryness to yield 5-methoxycarbonyl-8-(3-pyridyl)-oct-7-enenitrile.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29](=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30](Cl)=[O:31].O>C(OC(C)C)(C)C>[CH3:28][C:29](=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:31]
Reactant: c1ccc(CN2CCC(Nc3ccccc3)CC2)cc1
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=Cc1ccccc1)C(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a mixture of N-(1-benzyl-4-piperidinyl)aniline (6.4 g), diisopropyl ether (70 ml) and triethylamine (4.8 ml) is added at 70° C. a solution of α-methylcinnamoyl chloride (4.9 g) in diisopropyl ether (10 ml). After stirring at the same temperature for 30 minutes, water is added to the reaction solution and the mixture is extracted with ethyl acetate. The extract is concentrated by distilling off the solvent and to the resulting residue is added diethyl ether and the formed crystals are separated by filtration to give N-(α-methylcinnamoyl)-N-(1-benzyl-4-piperidinyl)aniline (8.9 g), m.p. 150°-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12]([OH:17])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:3](=[C:2]([NH:1][CH:14]([CH3:15])[CH2:13][C:12]([OH:17])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C/C=C/C(=O)O
Reactant: Nc1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)Nc1cccc2ncccc12
Yield: 51 %

Procedure:
A mixture of 5-aminoquinoline (9.9 g, 0.069 mol) and crotonic acid (8.9 g, 0.103 mol) in toluene (35 ml) was stirred at reflux for 48 h. The reaction mixture was allowed to cool to ambient, added to water (500 ml) and the pH adjusted to 9 to 10 by the addition of 2N sodium hydroxide. The reaction mixture was screened and the filtrate extracted with diethyl ether (3×100 ml). The pH of the aqueous layer was first adjusted to pH2 with concentrated HCl and then to pH7 with calcium hydroxide. The precipitate which formed was collected by filtration, washed first with water (200 ml) and then with acetone (200 ml) before being dried to give 8.1 g of a cream solid.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([OH:20])=O)[C:7]=2[C:6]([CH3:21])=[N:5]1)([CH3:3])[CH3:2].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30]>>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:18]([C:8]1[C:7]2[C:6]([CH3:21])=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=[C:10]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)[CH:9]=1)=[O:20]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C)c2cc(-c3cn[nH]c3)cc(C(=O)O)c12
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cn[nH]c3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was prepared from 1-isopropyl-3-methyl-6-(1H-pyrazol-4-yl)-1H-indazole-4-carboxylic acid and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.059 g, 0.387 mmol) in the same manner as described for example 80 (step c) wherein the contents were stirred at RT for 5 h. The product was collected as a pale yellow solid (30 mg, 20%). 1H NMR (DMSO-d6, 400 MHz): δ 1.563 (d, J=6.8 Hz, 6H), 2.207 (s, 3H), 2.455 (s, 3H), 2.556 (s, 3H), 4.616 (d, J=6 Hz, 2H), 4.781-4.798 (m, 1H), 5.899 (s, 1H), 7.236 (s, 1H), 7.488 (s, 1H) 7.522 (s, 1H), 7.797 (d, J=9.6 Hz, 2H). LCMS (ES+) m/z: 419.45.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+]>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=3)=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(Sc3ccc(S(C)(=O)=O)cn3)cc2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCON=C(CC)C1=C(O)CC(c2ccc(Sc3ccc(S(C)(=O)=O)cn3)cc2)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of 4.60 g (0.0107 mol) of 2-propionyl-3-hydroxy-5-(4-(5-(methylsulfonyl)-2-pyridylthio)phenyl)cyclohex-2-en-1-one in 100 mL of methylene chloride and 100 mL of 95 percent ethanol was added 1.35 g (0.0139 mol) of ethoxyamine hydrochloride and 1.31 g (0.0160 mol) of anhydrous sodium acetate. The slurry was stirred at ambient temperature for 12 hours and diluted with 100 mL of methylene chloride and washed thrice with 150 mL portions of water. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo leaving 4.8 g (94.7 percent of theoretical) of the crude product. The product was purified by column chromatography using 5:95 acetone:methylene chloride as eluent and then trituration with diethyl ether affording 2.60 g (51.3 percent of theoretical) of the above named title compound, melting at 125.5°-128.5° C.; 1H NMR (CDCl3): δ 1.05-1.40 (m, 6H, CH3CH2 -- and CH3CH2O--), 2.55-3.55 (m, 11H, ring protons, CH 3 SO2 --, CH3CH2 --), 4.10 (q, 2H, CH3CH2O--), 6.9-8.85 (m, 7H, ArH), 15.0 (broad s, br, 1H, OH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2)#N.P([O-])([O-])(O)=[O:13]>O.C(O)(=O)C.N1C=CC=CC=1.[Ni].O>[NH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=P([O-])([O-])O
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=Cc1ccc2[nH]ncc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
5-Cyanoindazole (2.32 g) [Hailey etc Synthetic communications, (1997), 27 (7), 1199-1207] was dissolved in a mixture of water (16.7 ml ), glacial acetic acid (16.7 ml ) and pyridine (33.4 ml) under a atmosphere of nitrogen. Sodiun hydrogen phosphate (4.64 g) was added to the mixture followed by raney nickel/ water (2 g/ml). The reaction mixture was heated to 50° C. for 5 hrs and then allowed to cool to room temperature and stirred for 18 hrs. The catalyst was then filtered off and washed with pyridine and water. The pH of the solution was adjusted to 9.0 with sodium carbonate and the product extracted with ethyl acetate (×2). The organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude solid was purified by washing with toluene to afford the title compound as a beige solid (2.36 g).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C([N:14]1[CH:18]([CH2:19][OH:20])[CH2:17][O:16][C:15]1=[O:21])C.Cl.N1C=CC=[CH:25][CH:24]=1>[Cl-].[Na+].O>[CH2:24]([C:18]1([CH2:19][O:20][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH2:17][O:16][C:15](=[O:21])[NH:14]1)[CH3:25]
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN1C(=O)OCC1CO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC(=O)N1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Tosyl chloride (142.2 g, Aldrich) was added to an ice-chilled solution of the product from step (a) (102.7 g) dissolved in pyridine (175 ml. Aldrich). The reaction mixture was stirred at ice bath temperature for six hours, then allowed to come to room temperature. The heterogeneous mixture was added to 1500 ml of a solution of brine and 1N HCl, stirred until solids appeared, filtered and washed with diethyl ether to give 194.6 g of a beige solid as the title product. 1H NMR consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[C:24]#[CH:25]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCn1ccc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nnc2n1-c1sc(C#CCN3CCc4ccccc4C3=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was synthesized by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 3,4-dihydro-2.(2-propynyl)1(2H)-isoquinolinone [ref. W. Schneider et al. Arch. pharm., 291, 560 (1958)]under the conditions described in EXAMPLE 37. The product was isolated by chromatography over the 50-fold amount of solica gel using tetrahydrofuran/hexane 4:1 for elution. The clean fractions were combined and evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 2-{3-[4-(2-chlorophenyl) 9 methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2.yl]-2-propynyl}-3,4-dihydro-1(2H)-isoquinolinone with m.p. 164°-166°.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]1[O:23][CH2:22][CH:21]([N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)[CH2:20][C:19]2=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]1[O:23][CH2:22][CH:21]([N:30]3[CH2:31][CH2:32][CH:33]([NH:36][CH2:12][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)[CH2:34][CH2:35]3)[CH2:20][C:19]2=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CO3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NCc2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (28 mg, 0.14 mmol 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine (50 mg, 0.14 mmol, 1.0 eq) in 1,2-dichloroethane (3 mL) and methanol (1.5 mL), followed by acetic acid (9 μL, 0.16 mmol, 1.15 eq) and sodium cyanoborohydride (12 mg, 0.18 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and a saturated sodium hydrogen carbonate aqueous solution (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 6-{[1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamino]-methyl}-4H-benzo[1,4]thiazine-3-one as an off-white lyophilizated solid (25 mg, 36% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Cl-].[NH4+]>O.CCO.[Fe]>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)N1CCC(Oc2ccc(N)cc2)CC1
Yield: 69.9 %

Procedure:
A mixture of 1-methanesulfonyl-4-(4-nitro-phenoxy)-piperidine (9.07 g, 30.2 mmol), iron powder (˜325 mesh, 5.05 g, 90.6 mmol), ammonium chloride solution (6.46 g, 120.8 mmol) in water (50 mL) and EtOH (IMS grade, 150 mL) was heated at reflux for 2 hours. The cooled mixture was filtered through Celite® washing with DCM and the organic solvent removed under vacuum. The remaining aqueous was diluted with water and extracted into DCM (3×). The combined extracts were dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-10% EtOAc in DCM) followed by trituration from Et2O afforded the title compound (5.71 g, 70%) as an off white solid. 1H NMR (300 MHz, DMSO) δ 6.70 (d, J=8.5 Hz, 2H), 6.50 (d, J=8.5 Hz, 2H), 4.65 (br s, 2H), 4.22 (m, 1H), 3.32 (m, 2H), 3.07 (m, 2H), 2.88 (s, 3H), 1.90 (m, 2H), 1.67 (m, 2H). LCMS (m/z, Method A) ES+ 271.0 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:19]=[C:18]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:33])[C:9](=[O:34])[NH:8]2)(O)=[O:2].C(N1C=CN=C1)([N:37]1C=CN=C1)=O.N>O1CCCC1.C(OCC)(=O)C>[C:1]([C:4]1[S:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:19]=[C:18]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:33])[C:9](=[O:34])[NH:8]2)(=[O:2])[NH2:37]
Reactant: O=C(O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 5-carboxy-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (14 mg) in tetrahydrofuran (1 mL) was added 1,1′-carbonylbis-1H-imidazole (9 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: methylene chloride/ methanol=10/1) to give the title compound (13 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([Cl:36])[CH:23]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCCC1>[NH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([Cl:36])[CH:23]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CNC(=O)OC(C)(C)C)cc34)cc2Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CN)cc34)cc2Cl)cn1
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a solution of 4.42 g of E-(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy) phenylamino]-quinazolin-6-yl}-allyl)-carbamic acid tert-butyl ester in 21 mL of tetrahydrofuran was added 21 mL of 2 N hydrochloric acid. The mixture was heated at 60° C. for 3 hours, cooled to room temperature and basified with 10% aqueous potassium carbonate. Methylene chloride was added to the aqueous mixture and a solid precipitated. The solid was filtered and dried to yield 2.98 g of E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl pyridin-3-yloxy)-phenyl]-amine. 1H NMR (d6 DMSO): δ 8.62 (s, 1), 8.53 (m, 1), 8.26 (m, 2), 7.99 (m, 1), 7.89 (m, 1), 7.77 (m, 1), 7.30 (m, 3), 6.67 (m, 2), 3.44 (m, 2), 2.47 (s, 3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>CN(C=O)C>[CH2:16]([N:15]1[C:11]([O:10][C:4]2[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:3]=2)=[CH:12][CH:13]=[N:14]1)[CH3:17]
Reactant: Sc1ccccn1
Reactant: CCn1nccc1Oc1cc(Br)cnc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1C#N
Reaction time: 1 h
Yield: 93.3 %

Procedure:
5-Bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.1 g, 55 mmol) and cesium carbonate (17.9 g, 55 mmol) were combined with DMF (160 ml) and pyridine-2-thiol (6.1 g, 55 mmol) dissolved in DMF (40 ml) was added dropwise over 30 minutes. The mixture was then agitated for 1 hour, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified over silica gel (20-35% ethyl acetate/hexanes) to afford 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (16.6 g, 93% yield) as a white solid.