Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13].C([O-])([O-])=O.[K+].[K+].I[CH:22]([CH2:24][CH3:25])[CH3:23]>>[CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH:22]([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)I
Reactant: COC(=O)C=Cc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(C)Oc1cc(F)ccc1C=CC(=O)OC

Procedure:
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (120 mg) was reacted with K2CO3 (165 mg) and 2-iodobutan (0.12 ml) at 100° C. for 3 hrs as described above to yield title compound (105 mg)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O.C(O)C>O.Cl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:12]([C:18]([CH3:20])=[CH:17][C:16](=[O:21])[O:15]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Oc1cccc(NCc2ccccc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Product: Cc1cc(=O)oc2cc(NCc3ccccc3)ccc12

Procedure:
7-Benzylamino-4-methylcoumarin was synthesized from 3-benzylaminophenol and ethyl acetoacetate by the usual Peckmann reaction (anhydrous zinc chloride, absolute ethanol). Recrystallization from ethanol gave flat needles, m.p. 174.5°-175.5° C. The fluorescence maximum in water was 455 nm (excited 355 nm), in 10-2N HCl 458 nm. 1H nmr (60 MHz, CDCl3), δ2.36 (s, 3H, C--CH3), 4.45 (d, 2H, --CH2NH--, J=~5.5 Hz, collapses to a singlet when D2O added), 4.7-5 (1H, NH), 6.03 (s, 1H, H3), 6.57 (d, 1H H8), 6.63 (dd, 1H, H6, J56 =~9 Hz, J68 =~2 Hz), 7.45 (s, 5H, C6H5), 7.45 (d, 1H, H5, J56 =~9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:16]1[CH:20]=[CH:19][O:18][CH:17]=1)([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[OH:10].[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])=[C:3]([C:9]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)([C:16]2[CH:20]=[CH:19][O:18][CH:17]=2)[OH:10])[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(O)(c1ccoc1)c1ccoc1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccc(Br)cc1C(O)(c1ccoc1)c1ccoc1

Procedure:
Prepared from (2-amino-5-bromophenyl)[di(3-furyl)]methanol and chloroacetyl chloride generally according to procedure of described in example 1. 1H NMR (DMSO-d6): δ 10.69 (s, 1H), 8.14 (d, J=8.74 Hz, 1H), 7.69 (t, J=1.68 Hz, 2H), 7.54 (q, J=8.74 Hz, 1H), 7.51 (s, 1H), 7.32 (s, 2H), 7.02 (d, J=2.37 Hz, 1H), 6.43 (d, J=1.03 Hz, 2H), 4.26 (s, 2H); MS (ESI) m/z 408/410/412 ([M−H]−).
Reaction SMILES: Br[CH:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.Cl.[NH:13]1[CH:17]=[C:16]([CH2:18][C:19]([NH2:21])=[S:20])[N:15]=[CH:14]1>>[NH:13]1[CH:17]=[C:16]([CH2:18][C:19]2[S:20][C:2]3[O:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[C:10]=3[N:21]=2)[N:15]=[CH:14]1
Reactant: O=C1c2ccccc2OC1Br
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: c1ccc2c(c1)oc1sc(Cc3c[nH]cn3)nc12

Procedure:
Starting compounds: 2-bromo-3-coumaranone, 4-imidazolyl thioacetamide hydrochloride
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCCC.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Clc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccccn2)c1

Procedure:
A solution of 1H-pyrazol-4-carboxylic acid ethyl ester (1.25 g, 8.9 mmol), 2-chloropyridine (2.02 g, 17.8 mmol) and cesium carbonate (8.7 g, 26.75 mmol) in DMF (26.8 ml) was irradiated under microwave conditions at 180° C. for 10 min. The reaction mixture was extracted with diethylether, and the combined organic phases were washed with water and brine. The product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as white solid (0.81 mg, 42%). MS: M=218.2 (M+H)+
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[C:1]([CH2:2][CH2:3][N:11]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2][C:1]#[N:4])#[N:4]
Reactant: C=CC#N
Reactant: CCCCCCN
Product: CCCCCCN(CCC#N)CCC#N
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
20.1 g of acrylonitrile was added dropwise to an aqueous solution (150 ml) of 15.5 g of hexylamine at room temperature over 0.5 hours, and then the mixed solution was stirred at 70° C. for 3 hours. After standing to cool to room temperature, the mixed solution was extracted with 150 ml of ethyl acetate. The organic layer was separated from the solution, dried over anhydrous magnesium sulfate, and distilled off the solvent to obtain 31.4 g of a target compound as a colorless oily product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[CH2:15][CH2:16][CH2:17][O:18][C:19]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].FC1C2OCCOC=2C=C2OCC3([C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38]C3=O)C=12>>[N:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:40][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[CH2:15][CH2:16][CH2:17][O:18][C:19]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCC3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCC3

Procedure:
Following the procedure as described in EXAMPLE 5.25 and making non-critical variations using 7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one to replace 9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-(pyridin-2-ylmethyl)-7,8-dihydro-6H-spiro-[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one was obtained (87%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ8.46 (d, J=4.8 Hz, 1H), 7.71-7.77 (m, 1H), 7.37-6.88 (m, 6H), 6.64 (s, 1H), 6.18 (s, 1H), 5.03 (ABq, 2H), 4.72 (ABq, 2H), 4.04-3.84 (m, 2H), 2.66 (t, J=6.4 Hz, 2H), 1.88-1.67 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.1, 155.7, 154.3, 149.7, 149.4, 143.0, 137.5, 132.3, 129.1, 128.6, 123.9, 123.6, 123.4, 123.1, 122.0, 111.5, 110.4, 109.8, 79.3, 66.2, 58.0, 45.2, 25.2, 22.1; MS (ES+) m/z 384.8 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:3]1=[O:30].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:3]2=[O:30])=[O:40])=[CH:34][CH:33]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)NCc2ccccc2)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21)NCc1ccccc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-phenylmethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 260°-262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:27]([CH3:32])[C:28]([F:31])([F:30])[F:29])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:19][CH:20]([CH3:26])[C:21]([O:23]CC)=[O:22])[CH:15]=[CH:16][C:17]=2[F:18])=[O:10])=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:27]([CH3:32])[C:28]([F:31])([F:29])[F:30])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:19][CH:20]([CH3:26])[C:21]([OH:23])=[O:22])[CH:15]=[CH:16][C:17]=2[F:18])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Cc1ccc(F)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(Cc1ccc(F)c(NC(=O)C(c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
300 mg (0.633 mmol) of ethyl 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate (diastereomer mixture) were dissolved in a mixture of in each case 1.0 ml of methanol, THF and water, and 265.5 mg (6.33 mmol) of lithium hydroxide were added at 0° C. The mixture was stirred initially at 0° C. for 1 h and then at RT for 1 h. The solution was then diluted with water and acidified with 1 N hydrochloric acid (pH about 2). The aqueous phase was extracted three times with diethyl ether and once with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. This gave 294 mg (99.7% of theory) of the title compound as a mixture of four diastereomers.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:37])[C:33]([OH:36])([CH3:35])[CH3:34]>>[OH:36][C:33]([C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:29][N:31]=1)([CH3:35])[CH3:34]
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3cccc(C(F)(F)F)c3)C2)CC1
Reactant: CC(C)(O)C(N)=NO
Product: CC(C)(O)c1noc(C2CC(c3cccc(C(F)(F)F)c3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.24 mmol) of the compound from Example 152A and 45 mg (0.37 mmol) of the compound from Example 77A were reacted according to the General Method 2. Yield: 45 mg (35% of theory)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(NC(C)C)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reaction time: 0.17 h

Procedure:
In a 5 mL round-bottomed flask, Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) was solved in dichloromethane (500 μl) to give a white suspension. N,N-diisopropylamine (26.3 mg, 35.6 μl, 0.204 mmol) was added. and after 10 min stirring, methanesulfonyl chloride (11.7 mg, 7.89 μl, 0.102 mmol) was added and the reaction mixture was stirred over night at room temp. The reaction was quenched with 15 mL of saturated NaHCO3 and extracted with dichloromethane (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as white solid (18 mg, 64.3%), MS (ISP) m/z=410.3 [(M+H)+].
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.Br[C:43]1[CH:44]=[N:45][C:46]([N:49]([CH3:51])[CH3:50])=[N:47][CH:48]=1>>[ClH:27].[ClH:27].[CH3:50][N:49]([CH3:51])[C:46]1[N:47]=[CH:48][C:43]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH3:37])=[C:29]([CH:30]=2)[CH2:28][N:15]([CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][CH3:1])[CH2:10][CH2:11]2)[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])=[CH:44][N:45]=1
Reactant: CN(C)c1ncc(Br)cn1
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2cnc(N(C)C)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
The title compound was prepared from boronic acid (12) (25 mg, 42 μmol) and 5-bromo-2-dimethylaminopyrimidine (7.0 mg, 40 μmol) in accordance with Method L2.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:9]=1[C:10]([NH:12][CH2:13][C:14]1([C:26]2[C:31](O)=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:11]>CN(C=O)C.O>[Cl:7][C:8]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:9]=1[C:10]([NH:12][CH2:13][C:14]1([C:26]2[C:31]([O:4][CH3:1])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:18][CH2:19]1)=[O:11]
Reactant: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2O)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2OC)CC1

Procedure:
The [11C]MeI was trapped at 0° C. in a mixture of 2,4-dichloro-N-{[4-(3-hydroxypyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}benzamide (0.25 mg) in DMF (0.2 mL) containing Cs2CO3 (1-2 mg). This mixture was transferred to a vial at 100° C. and heated for five minutes. The reaction was diluted with H2O (0.8 μL) and purified by HPLC (Waters C18 XTerra, 7.8×150 mm, 5 μm, 15 minutes linear gradient 20% MeCN:(95:5:0.1) H2O:MeCN:TFA to 90% MeCN @ 3 mL/min, product elutes at 8.5 minutes). The product fraction was collected in a heated round bottom flask attached to a rotary evaporator, the solvent was removed and the product was transferred to a vial using physiologic saline to give to give 65 mCi of [11C] 2,4-dichloro-N-{[4-(3-methoxypyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}benzamide.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To 4.0 g (4.0 mmol) of resin-bound 5-fluoro-2-nitro-phenol prepared as generally described in Example 37 in 8.0 mL of DMF were added 1.34 g (8.0 mmol) of methyl 4-hydroxyphenylacetate, and 1.20 g (8.0 mmol) of K2CO3. The mixture was heated to 110° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each, and was hydrolyzed by LiOH/H2O/THF/ethanol at rt for 12 h to give the resin-bound [4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>N1CCCCC1>[O:14]1[CH2:13][CH:12]1[CH2:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: N#Cc1ccccc1OCC1CO1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of 2-cyanophenol (25.0 g., 0.21 mole), epichlorohydrin (117 g., 1.26 mole), and piperidine (10 drops) was stirred and heated at 115°-120° in an oil bath for 2 hours. The reaction mixture was then concentrated (90°/30 mm) to remove unreacted epichlorohydrin. The residue was diluted with toluene and taken to dryness twice to help remove the last traces of volatile material. The residual oil was dissolved in 263 ml. of THF, and the solution stirred at 40°-50° for 1 hour with 263 ml. of 1 N NaOH. The organic layer was separated and concentrated to give an oil which was combined with the aqueous phase. The mixture was extracted with CH2Cl2, and the extract dried (MgSO4) and concentrated to give 36.6 g (100%) of oil which slowly crystallized to a waxy solid. This product was used without further purification in Procedure 26A.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[CH:27]1([CH2:30][NH2:31])C[CH2:28]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:31][CH2:30][C:27]#[CH:28])=[O:24])=[CH:20][CH:19]=2)[CH:17]=1
Reactant: NCC1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: C#CCNC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 13 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using prop-2-ynlamine instead of cyclopropylmethylamine, to the title compound (15 mg, 13%) which was obtained as an off-white solid. MS: m/e=382.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([F:35])=[C:31]([CH:34]=1)[CH2:32]Br>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:1]([CH2:32][C:31]2[CH:34]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=2[F:35])[C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1cccc(N)c1
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COC(=O)c1cccc(N(Cc2cc(Cl)ccc2F)C2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
Using general procedure A with methyl 3-aminobenzoate (2.16 g, 14.3 mmol) and 1-Boc-4-piperidone (2.39 g, 12.0 mmol) followed by general procedure H with the resulting amine and 5-chloro-2-fluorobenzyl bromide (65%, 1.04 g, 3.0 mmol) gave 4-[(5-chloro-2-fluoro-benzyl)-(3-methoxycarbonyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white foam (911 mg, 47% over 2 steps).
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC(Cl)=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:46][C:47]([F:57])([F:56])[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>C1COCC1.CN1C(=O)CCC1>[I:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([NH:53][C:52]1[CH:54]=[CH:55][C:49]([O:48][C:47]([F:46])([F:56])[F:57])=[CH:50][CH:51]=1)=[O:16]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DIPEA (4.00 mL, 22.90 mmol) was added to a solution of 3-iodo-4-methylbenzoic acid (2 g, 7.63 mmol) and 2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU, 3.47 g, 8.40 mmol) in THF (18 mL) and NMP (2 mL) and the RM was stirred at RT for 30 min. 4-(Trifluoromethoxy)aniline (1.536 mL, 11.45 mmol) was then added and the RM was stirred at RT for 14 h. The solvent was evaporated off under reduced pressure and the residue was treated with aq. 1M HCl (50 mL) and extracted with TBME. The combined extracts were washed with aq. 1 M HCl (50 mL), aq. sat. Na2CO3, water, brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from n-heptane/EtOAc to afford the title compound as white needles. UPLC-MS (Condition 1) tR=3.42 min, m/z=421.9-422.9 [M+H]+, m/z=419.9-420.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 7.36 (d, J=8.3 Hz, 2H) 7.49 (d, J=8.3 Hz, 1H) 7.83-7.93 (m, 3H) 8.39 (d, J=2.0 Hz, 1H) 10.42 (s, 1H).
Reaction SMILES: Cl.[C:2]1([O:12][CH:13]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]3[O:20][C:21]([CH3:23])=[CH:22][C:14]2=3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[C:2]1([O:12][CH:13]2[CH2:19][CH2:18][N:17]([C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:38])[CH2:16][C:15]3[O:20][C:21]([CH3:23])=[CH:22][C:14]2=3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(o1)CNCCC2Oc1cccc2ccccc12
Reactant: O=C(O)c1cccnc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(o1)CN(C(=O)c1cccnc1)CCC2Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 115.9 %

Procedure:
4-(Naphthalen-1-yloxy)-2-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine hydrochloride (50 mg) prepared in Example 284 and 47 mg of triethylamine were dissolved in 1 mL of methylene chloride, then 39 mg of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimidehydrochloride (WSCD.HCl), 25 mg of nicotinic acid and 27 mg of 1-hydroxybenzotriazole were dropped thereinto successively and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured over 2 mL of water and the mixture was subjected to extraction with methylene chloride. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The resulting residue was purified by silica gel column chromatography to give 70 mg of 4-(naphthalen-1-yloxy)-2-methyl-7-(3-pyridylcarbonyl)-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.CN(C)[CH2:36][CH2:37][CH2:38][N:39]=[C:40]=[N:41]CC.Cl[CH2:46]Cl>CN(C)C1C=CN=CC=1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:41][C:40]2[CH:46]=[CH:36][CH:37]=[CH:38][N:39]=2)=[O:20])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: ClCCl
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)O)c(-c3ccccc3)nn12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)Nc3ccccn3)c(-c3ccccc3)nn12
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (60 mg) in dichloromethane (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.3 mg) and 2-animopyridine (20 mg) and the reaction mixture was stirred for 10 minutes. 4-Dimethylaminopyridine (2 mg) was added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of ethyl acetate and n-hexane (1:2) to give 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide (55.7 mg) as an yellow amorphous.