Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:42]([O:49][C:50]1[CH:57]=[CH:56][C:53]([CH:54]=[O:55])=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@@H:15]([O:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C@@H:54]([C:53]1[CH:56]=[CH:57][C:50]([O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:51][CH:52]=1)[OH:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(COc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](Oc1ccc(F)cc1)[C@H](O)c1ccc(OCc2ccccc2)cc1

Procedure:
The target compound (2.68 g) was obtained as a foam by carrying out the reaction and the post-treatment according to Reference example 20(b) using (S)-4-benzyl-3-[(4-fluorophenoxy)acetyl]oxazolidin-2-one (1.96 g) obtained from Reference example 22(a), a solution of dibutylboron triflate in dichloromethane (1M, 7.14 ml), triethylamine (1.08 ml) and 4-benzyloxybenzaldehyde (1.39 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[OH:30][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26][N:27]([C:42]([NH:41][CH3:40])=[O:43])[CH2:28][CH2:29]1
Reactant: CN=C=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH2Cl2 (1 mL). N,N-diisopropylethyl-amine (30 μL, 0.172 mmol) and methyl isocyanate (7 μL, 0.130 mmol) were added sequentially. The solution was stirred overnight at rt, then concentrated in vacuo on a Genevac. The resultant residue was dissolved in DMSO and purified via HPLC (30-64% CH3CN:H2O) to provide 4-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide (36 mg, 0.073 mmol). MS ESI: [M+H]+ m/z 493.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 7.93 (s, 2H), 7.44 (s, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.13 (s, 1H), 6.43 (d, J=4.8 Hz, 1H), 6.15 (s, 1H), 3.83-3.74 (m, 2H) (d, J=14.0 Hz, 2H), 3.07 (t, J=14.5 Hz, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.98-1.82 (m, 2H), 1.65 (d, J=13.9 Hz, 2H). rhSYK activity=+++
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6](I)[CH:5]=1.[CH2:16]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:17][C:18]#[CH:19]>CN(C=O)C.C(N(CC)CC)C.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>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([C:19]#[C:18][CH2:17][CH2:16][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:5]=1
Reactant: C#CCCOC1CCCCO1
Reactant: COC(=O)c1ccc(NC(C)=O)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(C)=O)c(C#CCCOC2CCCCO2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 148.8 %

Procedure:
To a degassed solution of 4-acetylamino-3-iodo-benzoic acid methyl ester (41.4 g, 130 mmol) in DMF (200 mL) and triethylamine (40 mL) were added PdCl2(PPh3)2 (3.99 g, 5.68 mmol) and copper (I) iodide (7.43 g, 39.0 mmol). A degassed solution of 2-but-3-ynyloxy-tetrahydro-pyran (30.1 g, 195 mmol) in DMF (100 mL) and triethylamine (20 mL) was added at 80° C. over a period of 1 hour under nitrogen. After the addition, the reaction mixture was stirred at 80° C. for 2 hours and then cooled to room temperature. Solvent was evaporated under reduced pressure. Ethyl acetate (200 mL) was added. The solid was filtered, and washed with ethyl acetate. The ethyl acetate solution was washed with brine, and dried over anhydrous Na2SO4. The organic phase was concentrated to dryness, to afford 66.8 g crude 4-acetylamino-3-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-benzoic acid methyl ester. This was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:28][NH2:29]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH3:25])=[CH:22][C:21]=3[CH3:26])[NH:29][N:28]=2)[CH:7]=[C:8]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]=1[OH:16])([CH3:14])([CH3:15])[CH3:13]
Reactant: NN
Reactant: Cc1cc(C)c(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C)c2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1
Yield: 90.1 %

Procedure:
A mixture of 18.3 g of 4-(2-chloro-4,6-dimethylnicotinoyl)-2,6-di-tertiary butylphenol, 11 g of hydrazine hydrate and 100 ml of pyridine is reacted and the product is treated in a similar manner as Example 1 to give 15.5 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 257°-258° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[NH:6][CH:7]=[N:8]2.[Mg+2].[Br-].[Br-]>N1C=CC=CC=1>[OH:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[NH:6][CH:7]=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]cnc2c1
Agent: [Br-]
Agent: [Mg+2]
Solvent: c1ccncc1
Product: COc1cc(O)c2c(=O)[nH]cnc2c1
Yield: 98.2 %

Procedure:
To a mixture of 5,7-dimethoxyquinazolin-4(3H)-one (4.80 g, 23.3 mmol) in pyridine (50 mL) at room temperature was slowly added MgBr2 (4.29 g, 23.3 mmol). It was heated to reflux for 1.5 hour. After solvent was evaporated under reduced pressure, to the residue was added a solution of AcOH (10 mL) in water (50 mL). A solid was precipitated. It was filtered, washed with water, and dried under vacuum with P2O5 to afford 5-hydroxy-7-methoxyquinazolin-4(3H)-one as solid (4.398 g, 98%). 1H NMR (300 MHz, DMSO-d6) δ 11.95 (br, 1H), 8.08 (s, 1H), 6.63 (s, 1H), 6.50 (s, 1H), 3.85 (s, 3H); LC-MS (ESI) m/z 193 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([C@@H:5]([F:30])[C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH2:3]1.[OH-].[K+]>CO>[OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([C@@H:5]([F:30])[C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)[C@H](F)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)[C@H](F)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A solution of methyl 3α-hydroxy-6α-fluoro-7-keto-5β-cholanoate (0.6 g, 1.42 mmoles) in methanol (46 ml) was added to a methanol solution of 10% potassium hydroxide (82 ml) and the resulting solution was kept under magnetic stirring overnight. Then methanol was removed under vacuum, the residue was taken up into water (50 ml), acidified with 10% hydrochloric acid and extracted with methylene chloride (3×30 ml). The combined organic phases were washed with brine (1×20 ml) and dried over sodium sulfate. After evaporation of the solvent, the residue (0.62 g) was subjected to flash chromatography on silica, eluting with methylene chloride/methanol 95:5, to obtain 0.55 g of a pure product (95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[N:39]1([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C1COCC1>[C:49]([O:48][C:46]([N:39]1[CH2:45][CH2:44][CH2:43][N:42]([C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[N:17]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:13]4[N:29]=[CH:28][S:27][C:14]=4[N:15]=3)[CH:19]=2)[CH2:41][CH2:40]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a stirred solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid (95 mg, 0.23 mmol) in 10 mL of THF was added DIEA (30 mg, 0.23 mmol) at room temperature. Then tert-butyl 1,4-diazepane-1-carboxylate (60 mg, 0.3 mmol), BOP-Cl (76 mg, 0.3 mmol) and DIEA (59 mg, 0.46 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, methanol:CH2Cl2=1:100) to give 4-{3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoyl}-[1,4]-diazepane-1-carboxylic acid tert-butyl ester (130 mg, 95.7%) as a yellow solid. LC-MS: 591.2 [M+H]+, tR=1.81 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH:7](O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2].S(Cl)([Cl:19])=O>N1C=CC=CC=1>[Cl:19][CH:7]([C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(O)c1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 97 g of ethyl 3-nitromandelate and 69 ml of thionyl chloride is stirred overnight at room temperature. Then a few drops of pyridine are added. After the evolution of gas has ceased, the mixture is stirred for about 2 hours at 100° C. Excess thionyl chloride is evaporated off in a water jet vacuum and the reaction mixture is distilled in a high vacuum. The title compound (b) is obtained in the form of a yellow oil with b.p. 134° C. at 0.06 mbar and with an Rf value of 0.5 on thin-layer silica gel plates in a methylene chloride system.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)[C:7]2[N:8]([C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:40][N:39]=[N:38][N:33]=3)=[CH:24][CH:25]=2)[C:7]2[N:8]([C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2c(-c3ccccc3)cnc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nn2c(-c3ccccc3)cnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 46 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-6-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step A) with trimethyltin azide according to the procedure of Example 1, Step G, gave a 46% yield of the title compound as a light brown solid, mp>70° C. (gradual): homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[N:11]([O-])=O.[Na+].Cl>O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=N[O-]
Reactant: COc1cc(N)ccc1C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1C
Yield: 52.2 %

Procedure:
The compound was prepared by a method analogous to that of Example 22, Step 1. The reaction of 100 g (0.73 mole) of 4-methyl-3-methoxyaniline and 50.5 g (0.73 mole) of sodium nitrite in the presence of 330 g (1.46 moles) of stannous chloride dihydrate, 1160 mL of concentrated hydrochloric acid and 250 mL of water gave 58.0 g of product as an oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>O1CCCC1.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C@H:9]([OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4[C@@H]5C[C@@H]5C5(OCCO5)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4[C@@H]5C[C@@H]5C5(OCCO5)[C@@]4(C)CC[C@@H]32)C1
Yield: 78 %

Procedure:
31 g of 3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7-one was reacted at room temperature within 1.5 hours in 310 ml of tetrahydrofuran with 31 g of lithium tri-tert.-butoxyaluminohydride. The reaction solution was diluted with diethyl ether, washed with potassium-sodium tartrate solution and water, dried, and evaporated. The residue was chromatographed on silica gel, thus obtaining 24.3 g 3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7β-ol, mp 199.5°-200° C. (acetone).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31](=[O:36])N(OC)C)=[O:24])([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31]([C:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:12][CH:11]=1)=[O:36])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: Fc1ccc(-c2ccco2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1ccc(-c2ccc(F)cc2)o1
Yield: 86.6 %

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-furan (1.8 g, 11.1 mmol) in THF (100 ml) at −35° C. was added n-butyl lithium (2.5M in THF) (4.54 ml, 11.4 mmol) over 3 min. The resultant mixture was stirred for 10 min. at −35° C. and then (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)piperidine (3.09 g, 11.4 mmol) in THF (10 ml) was added over 1 min. The resultant solution was stirred for 15 min. at −35° C. and then poured into saturated ammonium chloride (120 ml) and extracted with ethyl acetate (3×50 ml). The combined organics were washed with saturated aqueous sodium hydrogen carbonate (50 ml) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to give the title compound as a golden oil (3.59 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:5]([NH2:12])[CH:6]=[N:7]2.[CH:18](OCC)(OCC)OCC.Cl.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[C:3]2[C:4]3[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:18]=[N:12][C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)CNc1c(N)cnc2cccc(Br)c12
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)Cn1cnc2cnc3cccc(Br)c3c21

Procedure:
A mixture of 5-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine (1.0 g, 3.4 mmol), triethyl orthoformate (0.9 mL, 5 mmol), and pyridine hydrochloride (117 mg, 1.0 mmol) in acetonitrile (17 mL) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 9-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:17][OH:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH3:24][O:25][C:26]([C:28]1([C:31](OC)=[O:32])[CH2:30][CH2:29]1)=[O:27].C(O)(=O)C>O1CCCC1.O>[CH3:24][O:25][C:26]([C:28]1([C:31]2([OH:32])[O:18][N:17]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:10]2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: COC(=O)C1(C(=O)OC)CC1
Reactant: COc1ccc(C(Cc2ccccc2)=NO)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1(C2(O)ON=C(c3ccc(OC)cc3)C2c2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
1-(4-Methoxy-phenyl)-2-phenyl-ethanone oxime, which may be produced as in Example 137 (110 g, 456 mmol, 1 equiv) is dissolved in tetrahydrofuran (825 mL), and the solution is cooled to about 0 □C in an ice/isopropyl alcohol bath. Butyllithium (2.5 M in hexane, 383 mL, 957 mmol, 2.1 equiv) is added at a rate to keep the temperature below 10 □C (about 1 hour addition time). The solution is allowed to stir for about 15 minutes. Cyclopropane-1,1-dicarboxylic acid dimethyl ester (86.5 g, 547 mmol, 1.2 equiv.) is added rapidly, and the reaction is allowed to stir for about 15 minutes. The reaction is quenched by the addition of acetic acid (65.3 mL, 1140 mmol, 2.5 equiv), and water (200 mL) is added. The mixture is allowed to sit overnight. The water layer is removed, and the organic layer is washed with water (300 mL). Toluene (100 mL) is added, and the organic layer is concentrated to give crude title compound, 1-[5-hydroxy-3-(4-methoxy-phenyl)-4-phenyl-4,5-dihydro-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester, which may be used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][O:29][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCOCc4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.080 g, 0.19 mmol) in DMF (1 mL) was added sodium hydride (60% in mineral oil, 0.010 g, 0.24 mmol), followed by benzyl bromide (0.024 mL, 0.20 mmol), and the reaction was stirred at room temperature for 1 hour. After aqueous workup, the crude material was purified by silica gel chromatography (0-15% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:37])[CH:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][C:20]=1[CH3:21])[C:11](O)=O)[CH3:7].C=O.C(OCC)(=O)C>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:37])[C:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[CH:19][C:20]=1[CH3:21])=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)O
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Diethylamine (0.26 g, 2.67 mmol) was added a mixture of 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.0 g, 2.2 mmol) and 37% aq. solution of formaldehyde (0.24 g, 3.00 mmol) in methylene chloride (2 mL) at 0° C. The mixture was stirred for 16 h at room temperature and ethyl acetate was added. The organic layer was washed with water and 5% NaHCO3 and dried. Concentration under reduced pressure followed by flash chromatography (toluene/ethyl acetate, 3:1→1:1) gave 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.81 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]1([CH3:30])[CH3:29].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3([CH3:30])[CH3:29])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C(C)(C)C1
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 600 mg, 2.186 mmol), (R)-tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (549 mg, 2.404 mmol) and DIPEA (0.764 mL, 4.37 mmol) in DMA (3.0 mL) was heated at 90° C. for 3 h. The mixture was cooled and added to crushed ice, stirred for 30 min, then extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine, filtered and concentrated to afford brown oil, which was added to water and stirred for 2 h to afford a solid which was collected by vacuum filtration and dried to afford the title compound as a tan solid (546 mg, 1.17 mmol, 54%). HPLC (Method B) retention time=3.91 min. LCMS (m+1)=466/468(1:1).
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:30])=[NH:6]>[Ni].CO>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:30])(=[NH:4])[NH2:6]
Reactant: COc1ccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)cc1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cn(N=C3CCc4c(C(=N)N)cccc43)c(N)n2)cc1

Procedure:
Analogously to Example 2, approximately 2 g of Raney nickel are added to a solution of 5.8 g (0.00129 mol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(4-methoxyphenyl)-imidazole dihydrochloride in 600 ml of methanol, and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered and the filtrate is concentrated. The product that has crystallised out is filtered off with suction and recrystallized from methanol, yielding the title compound in the form of the monohydrate, m.p. >220° C., 1H-NMR (DMSO): δ=9.56 (d, 4H); 8.33 (d, 1H); 7.99 (s, 1H); 7.94 (s, 2H); 7.75-7.84 (m, 3H); 7.64 (t, 1H); 7.04 (d, 2H); 3.80 (s, 3H), 3.40 (m, 4H).