Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)=[O:4].[CH3:14][CH:15](C)[CH2:16]N(C=CC)CC(C)C.CN(C)C=O.[OH:31][CH2:32][C:33]([CH3:37])([CH2:35][OH:36])[CH3:34]>O>[CH3:34][C:33]1([CH3:37])[CH2:35][O:36][CH:14]([CH:15]([CH3:16])[CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][CH:6]=2)=[O:4])[O:31][CH2:32]1
Reactant: CC(C)(CO)CO
Reactant: CCOc1ccc(C(=O)CBr)cc1
Reactant: CC=CN(CC(C)C)CC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)CC(C)C2OCC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
2-Bromo-1-(4-ethoxyphenyl)ethan-1-one (4.0 g) and N,N-bis(2-methylpropyl)-1-propenylamine (4.0 g) were added to 16 ml of dimethylformamide under an atmosphere of nitrogen and the mixture was stirred between 50° C. and 55° C. for 2 hours. To the reaction mixture were added successively 1.6 g of paratoluenesulfonic acid and 2.1 g of neopentyl glycol and the mixture was stirred between 50° C. and 60° C. for 3 hours. After addition of 8 ml of water to the reaction mixture and cooling the reaction mixture to the room temperature, crystals precipitated. These crystals were isolated by filtration to give 3.7 g (yield 72%) of the title compound as white crystals. The 1H-NMR spectrum of the product is substantially identical with that of the product of Example 1.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:12].[Na+].Cl>CN1CCN(C)C1=O.O>[F:11][C:9]1[CH:10]=[C:2]([OH:12])[C:3](=[CH:7][CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1ccc(F)cc1O
Temperature: 135 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A solution of 2,4-difluorobenzoic acid (100 g, 0.63 mol) in 1,3-dimethyl-2-imidazolidinone (1,400 mL, 0.45 M) was treated with sodium hydroxide (88 g, 2.2 mol) and heated to 135° C. After stirring for 4 h, the solution was cooled 0° C., disolved in water (100 mL), and transferred to a 5 L Erlenmeyer flask and carefully treated with aq HCl (2,800 mL, 2 N). After filtering off the crude product, the precipitate was disolved in ethyl acetate, dried over sodium sulfate and decolorizing charcol, and filtered. The solution was concentrated under reduced pressure and recrystallized from ethyl acetate and heptane to give 4-fluorosalicylic acid (2 crops, 67 g, 68%) as off-white needles. mp: 188–189° C.; Rf 0.26 (20% methanol in dichloromethane).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH:32]5[CH2:36][CH2:35][O:34][CH2:33]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([O:39]CC)=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH:32]5[CH2:36][CH2:35][O:34][CH2:33]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([OH:39])=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(OC3CCOC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(OC4CCOC4)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylate (0.240 g, 0.424 mmol) in tetrahydrofuran (12 mL) and methanol (4 mL) at room temperature was added a solution of lithium hydroxide hydrate (0.071 g, 1.696 mmol) in water (2 mL). The resulting mixture was stirred at room temperature for 1.5 hr, and then concentrated under vacuum to almost dryness. To the residue was added water (8 mL), and the mixture was neutralized with 1N HCl to pH 4-5. The insoluble product (0.195 g, 0.363 mmol, 86% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[ClH:16].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([Cl:16])=[O:13])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1ccnc2ccccc12
Yield: 78 %

Procedure:
2-[4'-(5"-nitrofuryl-2")-1,3-butadienyl]quinoline-4-carboxylic acid chloride hydrochloride was prepared as described in Example 1 from 2-[4-(5"-nitrofuryl-2")-1,3-butadienyl]quinoline-4-carboxylic acid and thionyl chloride with the yield of 78%, m.p. 230°-232° C. (with decomposition).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CC(C)([O-])C.[K+].Br[CH2:14][CH2:15][CH2:16][Cl:17].O>CN(C=O)C>[Cl:17][CH2:16][CH2:15][CH2:14][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2.0 g (10.31 mmol) 4-iodopyrazole were dissolved in 20 ml DMF and 1.22 g (10.8 mmol) potassium t-butoxide was added. The mixture was stirred for 1 hour at room temperature and 1.06 ml (10.83 mmol) 1-bromo-3-chloropropane were added. A white precipitate appeared rapidly. After 30 minutes 50 ml water was added and the reaction mixture was extracted twice with 100 ml hexane. The combined organic layers were dried over MgSO4 and the solvent was removed to give 2.65 g of the desired product as a colourless oil. MS (ISP): 270.1 (MH+). 1H-NMR (CDCl3): 2.31 (quint, 2H), 3.47 (t, 2H), 4.32 (t, 2H), 7.48 (s, 1H), 7.53 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[N:51][N:52]([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=3)[CH:53]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][N:52]1[CH:53]=[C:49]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:7]=[CH:2][C:3]([CH:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:32][CH2:33]5)=[CH:4][CH:5]=4)[CH:9]=3)[N:14]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH:15]=2)[CH:50]=[N:51]1
Reactant: CC1(C)OB(c2cnn(Cc3ccccn3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccn4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 39.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (150 mg, 0.52 mmol) was coupled with 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (intermediate 64H) (180 mg, 0.63 mmol) using Pd(PPh3)2Cl2 (18 mg, 0.026 mol) and sodium carbonate (165 mg, 1.56 mmol) in toluene/ethanol/water (10/10/2 ml) to afford 140 mg (97.2% yield) of the titled compound. MS: m/z=688.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[Cl:26][CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][CH2:27][CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: CC1(C)OB(c2cnn(CCCl)c2)OC1(C)C
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCCl)c3)ccc1-2

Procedure:
To a solution of the 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 51 (2.00 g, 34.75 mmol) and 1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in 8 mL of acetonitrile was added 7 mL of 2M of potassium carbonate in water followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.55 G, 0.476 mmol). This reaction mixture was heated on a Biotage microwave at 140 C for 10 minutes. The cooled reaction mixture was diluted with EtOAc, filtered to remove a black ppt, then washed with water ×1, saline ×1, then dried over Na2SO4, concentrated and purified by MPLC on a 12 gram silica column, eluting with 10-80% EtOAc/heptanes to give 8-[1-(2-chloro-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (1.6 g) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Br[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:24][CH:23]=2)[C:3]1=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CN2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 59.4 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 89 from 1.0 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1.01 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent gives 0.98 g of the expected product, which is used as such in the next step.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[C:25]([CH3:37])[NH:24][C:23]=1[CH:38]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)=[O:29])=[C:25]([CH3:37])[NH:24][C:23]=1/[CH:38]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrrole-2-carbaldehyde (174 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with acetone to give the titled compound as a pale orange solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)C=C.C(N(CC)CC)C.O>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
A mixture of 400 mg (0.8 mmol) of tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 0.2 ml of triethylamine, 0.5 ml of water and 78 mg of tris-(triphenylphosphine)rhodium(I) chloride in 10 ml of ethanol was stirred at reflux for 1 hour. The tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate formed in part (30% of theory), MS: 434 (M+H)+, was separated by chromatography and was used in the following step.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]C)=O.[NH2:11][C:12]([NH2:14])=[S:13].[OH-].[K+]>C(O)C.O>[SH:13][C:12]1[N:11]=[C:7]([OH:9])[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:14]=1
Reactant: NC(N)=S
Reactant: COC(=O)C1CCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1nc(S)nc2c1CCC2
Yield: 26.4 %

Procedure:
To a solution of the methyl 2-oxocyclopentanecarboxylate (40 g, 281 mmol) and thiourea (21 g, 281 mmol) in ethanol (200 ml) was added KOH (20 g, 356 mmol) in water (120 ml). The mixture was refluxed for 12 hour. The solvent was removed and the residue was quenched with concentrated HCl (25 mL). The precipitate was filtered, washed with water and dried to afford the 2-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12.5 g, 26%). MS (APCI+) [M+H]+168.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.ClC1[N:15]=[CH:14][C:13](CCl)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:15][CH2:14][CH3:13])=[CH:5][N:6]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: ClCc1cnc(Cl)s1
Solvent: ClCCl
Product: CCNCc1cnc(Cl)s1

Procedure:
The reaction procedure of Reference Example 17 was repeated except that crude 2-chloro-5-chloromethylthiazole was used in lieu of 6-chloro-3-pyridylmethyl chloride and that CH2Cl2 was used as the extractant. The procedure gave the title compound as a crude oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1ccco1
Product: COc1ccc(N2CCN(C(=O)Cc3ccco3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using furan-2-yl-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials. Product as an oil. LC/MS (Method B) 2.77 min, [M+1]+ 461. Potency class B.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>C(OCC)C>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3])=[O:13]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (4.23 g, 26.4 mmol) was slowly added dropwise to a solution of 1-(2,4-dichlorophenyl)ethanone (5.00 g, 26.4 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give 2-bromo-1-(2,4-dichlorophenyl)ethanone as an oil quantitatively.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([O:35]CC4C=CC=CC=4)=[O:34])[CH:27]=[CH:26]5)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Pd].O1CCOCC1.C(O)(=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([OH:35])=[O:34])[CH:27]=[CH:26]5)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)COc1ccc(-c2ccc3cc(C(=O)OCc4ccccc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 82.4 %

Procedure:
4.24 g (7.58 mmol) of the diester obtained in Example 4 in solution in the dioxane/acetic acid mixture (99/1) are treated with 800 mg of Pd-C (10%) at a pressure of 7 bar of hydrogen at 40° C. for 6 h. The reaction medium is then filtered on celite, evaporated, washed with water and recrystallized from the acetate/tetrahydrofuran mixture. 2.94 g (82%) of a solid are isolated, which solid melts at 283°-285° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.C([Si]([O:26][CH2:27][C:28]([CH3:32])([CH3:31])[C:29]#[CH:30])(C)C)(C)(C)C.[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>CC#N>[OH:26][CH2:27][C:28]([CH3:32])([CH3:31])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#CC(C)(C)CO[Si](C)(C)C(C)(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Solvent: CC#N
Product: CC(C)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2)CO
Yield: 28 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with tert-butyl[(2,2-dimethylbut-3-yn-1-yl)oxy]dimethylsilane to give the titled compound as a off-white solid (35 mg, 28%) after deprotection of the tert-butyldimethylsilyl ether (HF/MeCN).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30](O)=[O:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30]([NH2:40])=[O:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(=O)O)(c2ccccc2)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Yield: 46.8 %

Procedure:
A mixture of 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoic acid (500 mg, 1.12 mmol), HOBT (302 mg, 2.24 mmol), EDCl (440 mg, 2.24 mmol) and DIEA (1 mL) in anhydrous CH2Cl2 (10 mL) were stirred at 0□ under NH3. Then the solution was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (234 mg, yield 48%). 1H NMR (CDCl3): 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H). LC-MS Method 3 tR=1.3, min, m/z=447, 469; 1H NMR (CDCl3) 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[NH:5][C:4](=[O:26])[CH2:3]1.Br[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C([O-])(=O)C.[K+]>CN(C=O)C.CCOC(C)=O.[Cu]>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:26])[CH2:3]1
Reactant: Brc1cccnc1
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)Nc2ccccc21)c1ccccc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2cccnc2)c2ccccc21)c1ccccc1
Temperature: 125 °C
Yield: 64.9 %

Procedure:
To a stirring solution of 3.3 g (9.39 mmol) of 2-(2,4-Dioxo-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 47, in 25 mL of DMF is added 2.97 g (18.78 mmol, 2 equiv.) of 3-bromopyridine, 1.84 g (18.78 mmol, 2 equiv.) of potassium acetate, and 1.19 g (18.78 mmol, 2 equiv.) of copper powder. The suspension is heated to 125° C. for 8 h and then cooled to RT. It is diluted with 500 mL EtOAc and filtered through a bed of celite. The filtrate is washed with H2O (2×500 mL), conc. NH4OH (2×350 mL) and then dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 2.61 g of the title compound as an oil: 1H NMR (CDCl3, 300 MHz) δ8.50 (m, 1H), 7.78 (d, 1H, J=9), 7.48-7.25 (m, 7H), 7.14 (t, 1H, J=8), 6.88 (d, 1H, J=10), 5.06-4.95 (m, 1H), 4.30-4.09 (m, 3H), 3.54 (q, 1H, J=13, 6), 1.7 (s, 1H), 1.42 (d, 2H, J=6), 1.10 (dd, 6H, J=9,2).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>C(OCC)C>[CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+:10]
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCOCC
Product: [Li+]
Product: c1ccc2[cH-]ccc2c1

Procedure:
In a 500-mL flask were placed 32.62 g of technical grade indene (92.5 wt %) and 165 mL of diethyl ether. To this stirred solution were added 99.5 mL of 2.5 M n-BuLi (in hexanes) over 45 minutes. The reaction was exothermic and the solvent refluxed spontaneously and was returned to the reaction by an ice-water cooled condenser. A clear orange solution of lithium indenide was obtained.