Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].N[C:20]1C=CC(O)=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[CH3:20])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: Nc1ccc(O)cc1
Product: CNC(=O)c1cc(Oc2ccc(N)cc2C)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 4-amino-2-methylphenol for 4-aminophenol. 1H-NMR (DMSO-d6) δ 8.73 (br q, J=4.8 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.02 (dd, J=5.7, 2.7 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 6.52 (d, J=3 Hz, 1H), 6.47 (dd, J=8.7, 2.7 Hz, 1H), 5.09 (s, 2H), 2.78 (d, J=3.3 Hz, 3H), 1.91 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a5) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: ClC(Cl)C.[NH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C([C@@H]1COC(=O)N1[C:26](=[O:48])[C@H:27]([CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[Cl:47])[CH2:28][CH:29]=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:40]([O:39][C:35]1[CH:34]=[C:33]([Cl:47])[C:32]([CH2:31][C@@H:27]2[CH2:28][CH2:29][N:5]([N:6]3[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]3)[C:26]2=[O:48])=[C:37]([Cl:38])[CH:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NN1CCC(O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1N1CCC(O)CC1
Yield: 87.2 %

Procedure:
Stir a mixture of dichloroethane (500 mL), N-amino-4-hydroxypiperidine (10.66 g, 91.88 mmol), (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (40.2 g, 76.57 mmol) and sodium triacetoxyborohydride (48.47 g, 229.71 mmol) at room temperature for 21 hours. Bring the reaction to 55° C. and is stir for 1 hour. Cool the reaction, dilute with dichloromethane, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica with a 100% ethyl acetate and 10% methanol in methylene chloride to afford 30 g (90%) of the titled product. MS (m/z): 449 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:19])[C:9]2[N:10]=[N:11][N:12]([CH2:14][Si](C)(C)C)[CH:13]=2)[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:19])[C:9]2[N:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:3]=1
Reactant: C[Si](C)(C)Cn1cc(C(F)c2cccc(Br)n2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C(F)c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-6-(fluoro{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)pyridine (500 mg, 1.46 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 4.37 mL, 4.37 mmol). The reaction was stirred at room temperature for 2 h. It was then diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (30-100% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[CH:12][N:11]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(-c2cccnc2)nc1Cc1ccccc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2cnc(-c3cccnc3)nc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A mixture of 110 mg of 4-benzyl-5-bromo-2-(3-pyridyl)pyrimidine, 59 mg of 3-ethynyl-3-quinuclidinol, 19 mg of tetrakis(triphenylphosphine)palladium(0), 10 mg of cuprous iodide, 0.14 ml of triethylamine and 1.5 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 100° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 2.5% methanol/ethyl acetate, to give 62 mg of the target compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:33])[CH3:32])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:35])([CH3:34])[C:5]1=[O:36].C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>O1CCCC1>[C:44]([NH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:32])[CH3:33])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:34])([CH3:35])[C:5]1=[O:36])(=[O:46])[CH3:45]
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN)C(=O)C(C)(C)O2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added triethyl-amine (0.040 ml), tetrahydrofuran (3 ml), acetyl chloride (0.04 ml) under ice-cooling, and the mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (80 mg) as colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:19]=[CH:18][N:17]=[CH:16]1>C(O)C>[Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: NCCCCCn1ccnc1
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)C(NCCCCCn1ccnc1)=N2
Yield: 19.5 %

Procedure:
A mixture of 5.3 g of 6-bromo-benz[cd]indole-2-thiol, 3.1 g of 5-(1H-imidazol-1-yl)pentanamine, 100 ml of ethanol and 6.3 g of mercuric acetate was reacted as described in Example 1, giving 1.5 g of the desired product, mp 138°-140° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.[OH-].[Na+]>ClCCl.CO>[CH3:29][C:25]1[CH:24]=[C:23]([NH:22]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and m-toluidine in dichloromethane and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])C(C#N)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.Cl.[OH-].[Na+].[C:33]([OH:36])(=[O:35])[CH3:34]>O>[Cl:19][C:6]1[CH:5]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:34]([C:33]([OH:36])=[O:35])=[N:21]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(=O)O
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 120 °C
Yield: 78 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (31) (136 mg, 0.312 mmol) in glacial acetic acid (3.0 mL) was treated with concentrated hydrochloric acid (0.345 mL). The reaction mixture was heated to 120° C. for 24 h. Starting material was still present by LC/MS. Additional concentrated hydrochloric acid (0.34 mL) was added. The reaction mixture was heated to 120° C. for another 24 h. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). At this time, the reaction was made basic by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ether (100 mL). The organic layer was discarded. The aqueous layer was acidified by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (32) (111 mg, 78%) as an orange solid which was used without further purification; LRMS for C17H13Cl2N5O6 (M m/z=454. Molecular Weight=454.2291; Exact Mass=453.0243
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH2:13][CH:12]2[CH2:21][CH3:22])=[O:10])[CH:4]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2>CC(O)CCC>[CH2:21]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:11]1[C:9]([C:5]1[N:6]=[CH:7][N:8]=[C:3]([NH:23][C:24]2[CH:25]=[C:26]3[C:39](=[CH:40][CH:41]=2)[CH2:38][C:28]2([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]2=[O:37])[CH2:27]3)[CH:4]=1)=[O:10])[CH3:22]
Reactant: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Cl)ncn1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CCCC(C)O
Product: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1

Procedure:
63 μL (0.25 mmol) 4M aqueous hydrochloric acid were added to 516 mg (2.00 mmol) (6-chloro-pyrimidin-4-yl)-(2-ethyl-6-fluoro-2,3-dihydro-indol-1-yl)-methanone and 611 mg (2.00 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 10 mL of 2-pentanol. The reaction mixture was refluxed for 6 h. The reaction mixture was evaporated down using the rotary evaporator and the residue was taken up in DMF. The purification was carried out by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:33](=[NH:36])[NH:34][OH:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[O:37]1[C:41](=O)NC=N1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]4)[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:33]3[NH:36][C:41](=[O:37])[O:35][N:34]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3F)nc3cc(C(=N)NO)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=c1[nH]cno1
Product: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1

Procedure:
Using a procedure analogous to that described in Example 3.94 (Step 3), and starting with 4-(5-chloropyridin-3-yl)-2-((2-fluorophenyl)amino)-N-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide, 3-(4-(5-chloropyridin-3-yl)-2-(2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (TFA salt) was prepared. MS ESI calc'd. for C27H25ClFNγO2 [M+H]+ 534. found 534. 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.27 (s, 1H), 8.83 (m, J=20.7, 2H), 8.39 (s, 1H), 7.81 (s, 1H), 7.65 (m, 1H), 7.26 (m, 3H), 3.85 (s, 2H), 1.44 (d, 2H), 1.07 (m, 2H), 0.71 (m, J=6.5, 7H), 0.54 (m, 2H)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH:55]1[CH2:58][CH:57]([OH:59])[CH2:56]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:55]2[CH2:58][CH:57]([OH:59])[CH2:56]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: OC1CNC1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (2.1 g, 5.3 mmol), prepared using procedures similar to those in U.S. Pat. No. 7,019,033, was taken into DMF (10 mL) followed by addition of PyBOP (2.6 g, 5.3 mmol) and the mixture was allowed to stir at room temperature over 15 minutes. Azetidin-3-ol hydrochloride (870 mg, 8.0 mmol) and DIPEA (1.85 mL, 11.2 mmol) was then added and the mixture was allowed to stir an additional hour at room temperature. The mixture was then partitioned with ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was then washed with water (3×) then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography using ethyl acetate: hexanes (5:1) eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (2.09 g, 87% yield) as a colorless amorphous solid. 1H NMR (400 MHz, CDCl3): 8.47 (s, 1H), 7.39 (dd, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.78 (m, 1H), 6.63-6.57 (m, 1H), 4.74-4.67 (m, 1H), 4.43-4.39 (m, 2H), 4.20-3.96 (br d, 2H), 2.50 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1F
Temperature: 4 °C
Yield: 91.8 %

Procedure:
A mixture of 2,4,5-trifluoronitrobenzene (5.4 g, 30.8 mmol), benzylalcohol (3.2 mL, 30.8 mmol) and potassium carbonate (6.4 g, 46.1 mmol), in DMF (20 mL), was stirred at ambient temperature for 72 h. Water (60 mL) was added and the mixture was cooled at 4° C. for 24 h. The resultant precipitate was filtered, rinsed with water and dried in vacuo to afford the product (7.5 g, 92%) as a pale yellow solid. 1H NMR (CDCl3) δ 7.90-7.94 (m, 1H), 7.38-7.44 (m, 5H), 6.85-6.90 (m, 1H), 5.22 (s, 2H).
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[O:1]([CH2:8][C:9]([O:11][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)COc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)ON1C(=O)CCC1=O
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A suspension of phenoxyacetic acid (15.2 g, 100 mmol) and N-hydroxysuccinimide (11.5 g, 100 mmol) in ethyl acetate (300 ml) was cooled in an ice bath, treated with N,N'-dicyclohexylcarbodiimide (20.6 g, 100 mmol) and stirred for 1 hour at 0° and then overnight at room temperature. The precipitate which formed was filtered; the filtrate was evaporated to dryness; and the residue was crystallized from ethyl acetate to yield 15.0 g of N-(phenoxyacetyloxy)succinimide.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[NH:15][CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCCn1cc(-c3ncc[nH]3)nc1-2
Reactant: ClCCN1CCOCC1
Product: Brc1ccc2c(c1)OCCn1cc(-c3nccn3CCN3CCOCC3)nc1-2
Yield: 51 %

Procedure:
9-Bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was alkylated with 4-(2-chloroethyl)morpholine to give 9-bromo-2-[1-(2-morpholinoethyl)-1H-imidazol-2-yl]-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (yield 51%. MS: 444.2) which was coupled under Suzuki palladium coupling conditions of Example 182 with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate to give 209. Yield 24%. MS: 432.1. 1H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 8.56 (d, J=2.3, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.51 (dd, J=8.4, 2.3, 1H), 7.21 (d, J=1.0, 1H), 7.04 (d, J=8.4, 1H), 6.89 (d, J=1.0, 1H), 4.72 (t, J=7.1, 2H), 4.50 (q, J=5.6, 4H), 3.48-3.40 (m, 4H), 2.73 (t, J=7.1, 2H), 2.46-2.36 (m, 4H)
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:18])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.9 %

Procedure:
Propanephosphonic acid cyclic anhydride (3.74 mL, 6.40 mmol) was added to a solution of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (500 mg, 2.134 mmol), tert-butyl 4-(methylamino)piperidine-1-carboxylate (457 mg, 2.134 mmol) and triethylamine (1.19 mL, 8.54 mmol) in dichloromethane (20 mL). The mixture was stirred at ambient temp for 3.5 hours and then concentrated under reduced pressure. The crude material was purified by silica chromatography (eluting with a solvent gradient from 2.5% methanol/97.5% dichloromethane to 5% methanol/95% dichloromethane) to afford the title compound (440 mg). MS (ESI) m/z 431.5 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:38]C(OC(C)(C)C)=O)[CH2:15][C@H:16]([OH:37])[C@@H:17]([NH:25][C:26](=[O:36])[C@H:27]([CH:33]([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.CO.[ClH:48]>O1CCOCC1>[ClH:48].[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]([NH2:38])[CH2:15][C@H:16]([OH:37])[C@@H:17]([NH:25][C:26](=[O:36])[C@H:27]([CH:33]([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cnccn2)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cnccn2)cc1)C(C)C

Procedure:
3.4 g (5.5 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane in 100 ml of 4N hydrogen chloride in dioxane (Aldrich) and 10 ml of methanol are stirred at room temperature for 2 hours. The solvents are removed; dioxane is added twice to the residue and evaporated off. The title compound is obtained in the form of a viscous oil, with the compound crystallising out on trituration with ether. M.p.: 194-198° C. TLC: Rf =0.35 (methylene chloride/methanol 10:1). HPLC20-100: tRet =9.77.
Reaction SMILES: Cl.[S:2]1[C:6]2[S:7][CH2:8][CH:9]([NH2:11])[CH2:10][C:5]=2[CH:4]=[CH:3]1.C(N(C(C)C)C(C)C)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C(Cl)Cl>[C:21]([NH:11][CH:9]1[CH2:8][S:7][C:6]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:10]1)(=[O:24])[CH2:22][CH3:23]
Reactant: NC1CSc2sccc2C1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NC1CSc2sccc2C1
Reaction time: 0.5 h

Procedure:
A mixture of 8.31 g of 5,6-dihydro-4H-thieno[2,3-b]- thiopyran-5-amine hydrochloride, 17.4 ml of ethyldiisopropylamine, 4.07 g of propionyl chloride in 80 ml of methylene chloride is kept for 30 minutes at room temperature. The reaction mixture is washed with 1N hydrochloric acid and then with saturated sodium bicarbonate solution, the organic layer is dried over magnesium sulfate and the solvent is removed in vacuo to yield N-propionyl-5,6-dihydro-4H-thieno[2,3-b]-thiopyran-5-amine. This is refluxed for 3 hours with 85 ml of 1M borane in tetrahydrofuran. Water and 3N hydrochloric acid are added and the mixture is heated briefly. Basification of the aqueous layer followed by extraction with ether affords an oil after removal of solvent. Addition of ethanolic hydrochloric acid affords N-propyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-amine hydrochloride, m.p. 107°-110°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[C:9]([C:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: CN1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c(C)c(C2=CCN(C)CC2)c1C
Temperature: 95 °C
Yield: 85.4 %

Procedure:
To a solution of 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (836 mg, 5 mmol) in acetic acid (10 mL) and TFA (5 mL) under nitrogen was added 1-methyl-piperidin-4-one (0.8 mL, 6.67 mmol). The mixture was then heated in a 95° C. oil bath for overnight. The reaction was concentrated, dissolved in ethyl acetate, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 1.12 g (85%) of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid ethyl ester.