Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]O)=[CH:22][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:8]([C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH2:27])=[CH:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCc1ccc(CCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(CCCCCCCCCCCC)cc1
Temperature: 25 °C

Procedure:
A 2 l round-bottom flask which had been provided with a water separator and a reflux condenser was charged initially with 1.2 liters of toluene and then with (p-dodecylphenyl)methylcarbinol (50.082 g=0.173 mol) and p-toluenesulphonic acid monohydrate (0.679 g=3.6 mmol). The mixture was heated to reflux with constant stirring and kept at boiling until no further water separated out. Once the reaction mixture had been cooled to room temperature, the organic phase was extracted by shaking twice with 500 ml each time of water and once with 250 ml of saturated sodium chloride solution. After drying over magnesium sulphate, the solvent was drawn off on a rotary evaporator. A yellow oil was obtained. Subsequently, the two batches were combined. The crude product was purified by column chromatography on 400 g of silica gel 60 with hexane as the eluent, and a fraction size of 100 ml was selected.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1.[C:36]([Si](C)(C)C)#[CH:37].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.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.[Cu]I>[C:36]([C:2]1[CH:3]=[CH:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1)#[CH:37]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)ccc3=O)CC2)C1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc(=O)n(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1
Reaction time: 8 h

Procedure:
N-({1-[4-(5-Iodo-2-oxo-2H-pyridin-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 8, Step C, 450 mg, 0.75 mmol), ethynyl-trimethyl-silane (Fluka, 100 mg, 1.02 mmol), Pd(Ph3P)2Cl2 (Aldrich, 0.02 mmol), CuI (Aldrich, 0.02 mmol) and TEA (1 mL) were mixed in THF (6 mL) at room temperature under argon. The reaction was stirred overnight. The solid was filtered off and the residue was partitioned between water and a chloroform/IPA “cocktail” (˜3:1, v/v). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was treated with TBAF (Aldrich, 1.0 N in THF, 2 mL) for 30 min. at room temperature. The solvent was removed and the residue was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.[NH2:30][NH2:31].O1CCCC1>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([NH:30][NH2:31])=[O:19])=[O:18])=[CH:11][C:10]([C:25]([F:26])([F:27])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(=O)NN)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.40 g of 2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.09 ml of hydrazine monohydrate and 20 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.26 g of 1-(3-chloro-2-pyridinyl)-N-[2-(hydrazinocarbonyl)-6-methylphenyl]-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].O.Cl>CO>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:9]=1
Reactant: COC(=O)c1ncc(C(F)(F)F)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(C(F)(F)F)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a stirring solution of 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A3) (1 g, 4.54 mmol) in MeOH (20 ml) was added 2M NaOH (0.182 g, 4.54 mmol). The orange solution was stirred at RT for 1 minute and then into water (10 ml). The solution was acidified to pH1 with the addition of 1M HCl and the product was extracted with EtOAc (150 ml). The organic portions were combined, washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound as an orange solid; LC-MS Rt=0.82 mins [M+H]+ 207.1 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 13.9 (1H, broad hump), 8.11 (1H, s), 7.59 (1H, s), 7.08 (2H, broad hump) (trace of EtOAc present but correlates to proposed structure).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=1.N>O>[Cl:34][C:29]1[CH:28]=[C:27]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Reactant: Fc1ccc(Br)cc1Cl
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62 substituting 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-bromo-2-chloro-1-fluorobenzene in place of 4-iodo-1-fluorobenzene (yield: 0.110 g, 74%). mp 153–156° C. 1H NMR (300 MHz, DMSO d6) δ 3.30 (s, 3H), 3.89 (bs, 2H), 7.02–7.07 (m, 4H), 7.59 (m, 1H), 7.65–7.72 (m, 4H), 8.07 (m, 2H), 8.12 (s, 1H). MS (DCI/NH3) m/z 487 (M+H)+, 504 (M+NH4)+. Anal. calc. for C24H17ClF2N2O3S.0.25 H2O: C, 58.65; H, 3.58; N, 5.64. Found: C, 58.41; H, 3.56; N, 5.36.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:18]([C:15]2[N:16]=[N:17][C:12]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=4[C:2]([F:25])([F:1])[F:26])[CH2:11][CH2:10]3)=[CH:13][CH:14]=2)=[O:20])[CH2:29][CH2:28]1
Reactant: O=C(O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 4, Step 3 from 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine-3-carboxylic acid and cyclopropylamine. 1H NMR (400 MHz, acetone-d6): δ 0.71-0.82 (m, 4H), 1.91-1.99 (m, 2H), 2.13-2.19 (m, 2H), 2.96-3.02 (m, 1H), 3.91-4.07 (m, 4H), 5.04 (m, 1H), 7.13 (t, 1H), 7.37 (m, 2H), 7.62-7.68 (m, 2H), 7.91 (d, 1H), 8.09 (s, 1H). MS (+ESI) m/z 407 (MH+).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[S:3](OC1C(C)(C)[C@H]2[C@](C)(CC=1)[C@@H]1[C@](C)([C@@]3(C)[C@H](CC1)[C@H]1[C@H](C(C)=C)CC[C@]1(NCCN1CCS(=O)(=O)CC1)CC3)CC2)(=[O:5])=[O:4].[O:49]=[C:50]1[CH2:54][CH2:53][CH:52]([CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH2:51]1>>[F:1][C:2]([F:48])([F:47])[S:3]([O:49][C:50]1[CH2:51][CH:52]([CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH2:53][CH:54]=1)(=[O:5])=[O:4]
Reactant: COC(=O)CC1CCC(=O)C1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: COC(=O)CC1CC=C(OS(=O)(=O)C(F)(F)F)C1
Yield: 50.1 %

Procedure:
The title compound was prepared following the procedure described in method 2 for the preparation of intermediate 1, Step 6, using methyl 2-(3-oxocyclopentyl)acetate as the reactant. (50.1% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.66 (q, J=2.1 Hz, 1H), 3.73 (br. s., 3H), 3.29-3.13 (m, 1H), 2.95-2.78 (m, 1H), 2.67-2.57 (m, 2H), 2.49-2.40 (m, 1H), 2.40-2.28 (m, 1H), 1.77-1.63 (m, 1H). 19F NMR (376 MHz, CHLOROFORM-d) δ −73.53 (s, 3F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([C:13]#[N:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(OCC)O[CH2:24][CH3:25]>>[CH2:11]([O:10][CH:8]([CH:7]([CH2:6][C:5]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]#[N:14])[O:9][CH2:24][CH3:25])[CH3:12]
Reactant: CCOC(=O)C(C#N)Cc1cc(OC)c(OC)c(OC)c1
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)C(C#N)Cc1cc(OC)c(OC)c(OC)c1
Yield: 82 %

Procedure:
A solution of ethyl 3,4,5-trimethoxybenzylcyanoacetate (14.7 g) in triethyl orthoformate (100 ml) has heated at reflux for 18 hours using a steam-jacketed column for continuous removal of ethanol. The solution was cooled, and most of the excess orthoformate was removed in vacuo. The crystals obtained were washed with ether and dried to yield colourless crystals of α-carbethoxy-of diethoxymethyl-β-(3,4,5-trimethoxy phenyl)propionitrile (16.3 g, 82%), m.p. 91°; nmr (CDCl3) δ1.13, 1.20, and 1.32 (triplets, 9, CH3CH2O-), 3.15 (s, 2, Ar-CH2 -C), 3.4-4.0 (m, 4, m, 4, CH3CH2 -O), 3.85 (s, 9, -C6H2 -(OCH3)3), 4.13 (q, 2, CH3CH2 -OCO), 4.80 (s, 1, -CH (OEt)2), and 6.55 (s, 2, aromatic H).Anal. Calcd. for C20H29NO7 : C, 60.74; H, 7.39; N, 3.54. Found: C, 60.56; H, 7.33; N, 3.64.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH2:15][CH2:16][OH:17].[CH2:18]([OH:20])[CH3:19].C1(C)C=CC=CC=1>C(O)(=O)C.O>[C:18]([O:17][CH2:16][CH2:15][C:8]1[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6])(=[O:20])[CH3:19]
Reactant: COc1cccc(O)c1CCO
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(O)c1CCOC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
1.0 mL (1.8 g, 18 mmol) of concentrated sulfuric acid was added dropwise to a solution of 0.27 g (1.6 mmol) of 2-(2-hydroxy-6-methoxyphenyl)ethanol in 5.0 mL of acetic acid while being cooled on an ice-water bath. This mixture was stirred under room temperature for 5 minutes and 6.0 mL (4.7 g, 102 mmol) of ethanol was added dropwise thereto. 20 mL of toluene and 20 mL of water were added to this mixture and after stirred for 5 minutes, the mixture was transferred to a separatory funnel and settled. The aqueous layer was separated and discarded and after the organic layer was washed with 100 mL of water twice, the solvent was evaporated to obtain 0.16 g of the title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3](C(O)=O)[CH:2]=1.C1C2C=CC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1C=C2
Product: C1=Cc2ccccc2Sc2ccccc21

Procedure:
In a similar manner, substituting 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid or dibenzo[b,f]thiepin-3-carboxylic acid for the carboxylic acid starting material employed in Step 1, there is obtained the corresponding 10,11-dihydrobibenzo[b,f]thiepin-3-(4-hydroxy-Δ3 -pyrrolin-3-yl-2,5-dione) or dibenzo[b,f]thiepin-3-(4-hydroxy-Δ3 -pyrrolin-3-yl-2,5-dione).
Reaction SMILES: [H-].[Na+].C(O)C.[CH2:6]([O:8][C:9](=[O:15])[C:10](OCC)=[O:11])[CH3:7].[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[CH3:17].Cl>C(OCC)C>[CH2:16]([O:18][C:19](=[O:29])[CH:20]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:10](=[O:11])[C:9]([O:8][CH2:6][CH3:7])=[O:15])[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)COc1cccc(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(Oc1cccc(F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105.7 %

Procedure:
60% NaH in mineral oil (19.5 g, 488.4 mmol) is covered with 600 ml of dry diethyl ether. Ethanol (28.1 ml, 444 mmol) is added dropwise within 25 min. Then oxalic acid diethyl ester (66 ml, 488 mmol) is added dropwise within 20 min. After 10 min stirring at room temperature, the mixture is heated to reflux. A solution of 107 (88 g, 444 mmol) in 80 ml of dry diethyl ether is added dropwise within 30 min and the mixture is allowed to reflux for 1 hour. After cooling down to room temperature, the reaction mixture is poured on 2M HCl (400 ml)/ice (400 g) and extracted with diethyl ether. The organic layers are dried over sodium sulfate, filtrated and evaporated. The crude product is purified by filtration over silica gel (ethyl acetate/hexane 1:1). Evaporation gave 140 g of an red oil. The mineral oil could be removed using a separatory funnel. Yield: 132 g (100%).
Reaction SMILES: C(OC1C=C(C=CC=1)CN(C1C=CC(C#N)=CC=1)N1C=NN=C1)C1C=CC=CC=1.[H-].[Na+].[C:32]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][N:41]2[CH:45]=[N:44][N:43]=[CH:42]2)=[CH:36][CH:35]=1)#[N:33].[Br:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][C:48]=1[O:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][O:57]1>CN(C=O)C.CCOC(C)=O>[O:57]1[CH2:58][CH2:59][CH2:60][CH2:61][CH:56]1[O:55][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:47]=1[Br:46])[CH2:51][N:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][CH:38]=1)[N:41]1[CH:42]=[N:43][N:44]=[CH:45]1
Reactant: BrCc1ccc(Br)c(OC2CCCCO2)c1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(Br)c(OC3CCCCO3)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
The title compound was prepared by adapting the method for 4-[(3-benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole using the following modifications. To a stirred suspension of NaH (60% dispersion in oil, 0.27 g, 6.78 mmol) in anhydrous DMF (10 mL) was added a solution of 4-[(4-cyanophenyl)amino]-4H-[1,2,4]triazole (1.26 g, 6.78 mmol) in anhydrous DMF (5 mL) and the mixture stirred at r.t. for 0.5 h. A solution of 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl bromide (2.61 g, 7.46 mmol) in anhydrous DMF (5 mL) was then added and the mixture heated at 80-90° C. for 3 h. The mixture was cooled, diluted with EtOAc (50 mL), washed with water (4×100 mL), brine (100 mL) and dried (Na2SO4). Concentration in vacuo and subsequent purification by flash column chromatography [SiO2, EtOAc (100%)] gave 4-[(3-(tetrahydropyran-2-yloxy)-4-bromobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole as a yellow oil (3.05 g, 99%); δH (270 MHz, CDCl3) 1.61-1.99 (m, 6H), 3.55-3.59 (m, 1H), 3.73 (m, 1H), 4.75 (d, J=14.6, 1H), 4.90 (d, J=14.6, 1H), 5.41 (m, 1H), 6.64 (AA′BB′, 2H), 6.69 (dd, J=8.2, 2.2, 1H), 7.00 (d, J=2.2, 1H), 7.49 (d, J=7.9, 1H), 7.57 (AA′BB′, 2H), 8.15 (s, 2H); LRMS (FAB+) m/z (rel. intensity) 456.1 (54, [C21H20N5O281Br+H]), 454.1 (54, [C21H20N5O279Br+H]); LC-MS (APCI+): tR=2.0 min, m/z 456.1 (94, [C21H20N5O281Br+H]), 454.1 (100, [C21H20N5O279Br+H]); HPLC: tR=2.21 min (94%); HRMS (FAB+): Found 454.08627 C21H21N5O279Br requires 454.08786.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][NH:27][CH3:28]>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([N:27]([CH3:28])[CH3:26])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CNC
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)C(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), a 40% aqueous solution of dimethylamine (0.410 g, 3.64 mmol), and carbon tetrachloride (25 ml) were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting semi-solid product was recrystallized by adding hexane to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-dimethyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.410 g, 36.4% yield).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=1)=[O:25]>O1CCOCC1>[CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:16]2[CH2:17][CH2:18][N:19]([C:29]3[N:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[N:27][CH:28]=3)[CH2:20][CH:21]=2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1c(Cc2ccccc2)nnc(C2=CCNCC2)c1C
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CC=C(c3nnc(Cc4ccccc4)c(C)c3C)CC2)cn1
Temperature: 160 °C
Yield: 29.9 %

Procedure:
To 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (170 mg, 0.358 mmol) is added 50% TFA in DCM. The reaction mixture is stirred for 10 min and concentrated to afford 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine as a yellow sticky solid (125 mg, 100%). To a solution of 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine (180 mg, 0.644 mmol) in dioxane is added methyl-5-chloropyrazine-2-carboxylate (222 mg, 1.29 mmol) and TEA (0.45 mL, 3.22 mmol) in a microwave tube. The reaction mixture is heated at 160° C. for 40 min in a microwave reactor. The mixture is concentrated to afford a brown oil and purified by prep HPLC, eluting with 10%-100% acetonitrile:water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (80 mg, 30%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[NH:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[N:14]1([C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([N:20]3[C:29]4[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)=[N:3][CH:4]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Reactant: COC(=O)c1ccc2c(c1)CCCN2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCCN2c1ncc(C(=O)N2CCOCC2)c(C(F)(F)F)n1
Yield: 55.8 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (200 mg), methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (323 mg), tris(dibenzylideneacetone)dipalladium(0) (19 mg), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25 mg), cesium carbonate (661 mg), and toluene (3 mL) was heated with reflux for 1 hour. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain methyl 1-[5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroquinoline-6-carboxylate (170 mg) as a yellowish white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:25]=2[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]3[O:28][C:29]2[C:30]([F:38])=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][CH:33]=[CH:32]3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:38][C:30]1[C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:17]=3)[N:22]=[CH:21][N:20]=2)=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[CH:33][NH:34]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.9 %

Procedure:
6-[1-(tert-Butoxycarbonyl)piperidin-4-yl]methoxy-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline (306 mg containing 10% w/w triphenylphosphine oxide) was dissolved in 1,4-dioxane (5 ml) and 4M hydrogen chloride in 1,4-dioxane (5 ml) was added. The mixture was stirred at ambient temperature for 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in methanol and adsorbed onto an Isolute SCX column, washed with methanol and then eluted with 7N ammonia in methanol to give 4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-(piperidin-4-ylmethoxy)quinazoline (215 mg, 66% over two steps).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21]([OH:22])[C:4]=2[N:3]=1.N1C=CN=C1.[CH3:34][C:35]([Si:38](Cl)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:37][C:35]([Si:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[O:22][C:21]1[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=1)([CH3:34])[CH3:36]
Reactant: Cc1nc2c(O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1nc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of crude 2-methyl-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazol-4-ol (200 mg), imidazole (73 mg) and TBDPSCl (162 mg) in dry DCM (30 mL) was stirred at room temperature for 1 h. LCMS analysis showed desired product so the solvent was removed in-vacuo. The residue was purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:2 to afford the TBDP ether desired product as a white solid (260 mg, 79%). 1H NMR (300 MHz, CDCl3) δ ppm 1.24 (s, 9H), 2.53-2.56 (m, 7H), 3.55 (t, 4H, J=4.8 Hz), 5.69 (s, 2H), 5.92 (d, 1H, J=1.8 Hz), 6.12 (d, 1H, J=1.8 Hz), 6.55 (d, 1H, J=7.5 Hz), 7.25-7.45 (m, 7H), 7.56-7.67 (m, 2H), 7.78 (d, 1H, J=8.7 Hz), 7.84-7.87 (m 4H), 7.94 (d, 1H, J=7.5 Hz), 8.06 (d, 1H, J=8.7 Hz); LC-MS: m/e=612 [M+1]+.