Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[C:3]1(/[CH:2]=[CH:1]/[C:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17]3[NH:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: C(=Cc1ccncc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C1=C(/C=C/c2ccccc2)CCN(Cc2nc3ccccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-styrylpyridine (4.0 g, 22.1 mmol) and 2-chloromethylbenzimidazole (3.7 g, 22.1 mmol) in dimethylformamide (20 ml) was heated at 110°-120° C. under a nitrogen atmosphere for 1.5 hours. The mixture was cooled to room temperature, diluted with ethanol (380 ml) and carefully treated with sodium borohydride (880 mg, 23.2 mmol). The mixture was stirred at room temperature for 2 hours, then heated at reflux for 1 hour before stirring at room temperature overnight. The ethanol was evaporated in vacuo and the residue partitioned between ethyl acetate (100 ml) and sodium carbonate (half saturated, 100 ml). The phases were separated and the aqueous was extracted with ethyl acetate (2×100 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give a reddish gummy residue which was purified by flash chromatography (eluting with 5% methanol in dichloromethane) to give a yellow gummy solid. The gum was triturated with ethyl acetate and recrystallised from ethyl acetate to give the title compound as a mustard solid (912 mg, 13%). M.p. 225°-227° C. (EtOAc); (Found: C, 79.74; H, 6.89; N, 13.47. C21H21N3 requires C, 79.97; H, 6.71; N, 13.32%); δH (DMSO-d6) 2.37 (2H, br s, tetrahydropyridinyl CH2), 2.69 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.17 (2H, br s, tetrahydropyridinyl CH2), 3.83 (2H, s, NCH2Ar), 5.91 (1H, s, CH=CR), 6.48 (1H, d, J 16.2 Hz, CHCHPh), 6.91 (1H, d, J-16.2 Hz, CHPh), 7.13-7.22 (3H, m, ArH), 7.29-7.33 (2H, m, ArH), 7.42-7.47 (3H, m, ArH), 7.54 (1H, m, ArH), and 12.31 (1H, br s, NH); m/z (CI+, NHs) 316 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:17]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:30]4[CH2:29][CH2:28][N:27]([C:17]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[O:18])[CH2:32][CH2:31]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Product: O=C(OCc1ccccc1)N1CCN([C@H]2CC[C@H](c3ccc4c(c3)OCO4)CC2)CC1

Procedure:
4-(1,3-Benzodioxol-5-yl)cyclohexanone and carbobenzyloxy piperazine were reacted as described in example 9 to give the product (31%, mp: 107°-108° C.). Calc'd for C25H30N2O4 : C, 71.07%; H, 7.16%; N, 6.64%. Found: C, 70.95%; H, 7.16%; N, 6.36%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[N:17]1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:30]#[C:29][CH:31]3[CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[N:17]1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1)C(F)(F)F
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1)C(F)(F)F
Yield: 7.6 %

Procedure:
The title compound was prepared according to the procedure described in Example 111 using N-(4-chloro-3-(3-(4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide (Intermediate-146, 0.300 g, 0.568 mmol), ethynylcyclopropane (0.056 g, 0.852 mmol), TBAF (0.444 g, 1.72 mmol), bis(triphenylphosphine)palladium(II) chloride (0.016 g, 0.022 mmol) and DMSO (3.0 mL) to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.75 (m, 2H), 0.90 (m, 2H), 1.55 (m, 1H), 4.43 (d, J=6.0 Hz, 2H), 7.38 (d, J=6.6 Hz, 1H), 7.46-7.51 (m, 3H), 7.64 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 10.06 (m, 1H), 12-13 (br s, 1H). MS (m/z): 461.12 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[NH:24][C:25]([CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]1)=[O:26].[OH:38][CH:39]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=1)[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH3:49])=[CH:44][CH:43]=1)=O.CN(C1C=CC=CN=1)C>CN(C)C=O.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[C:18]=1[NH:24][C:25]([CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37][CH:40]([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][CH3:49])=[CH:46][CH:47]=2)[C:39](=[O:38])[C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[O:36])[CH2:30][CH2:29]1)=[O:26]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(=O)O)CC1
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)C(OC(=O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)c2ccc(CC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
1,3-Dicyclohexylcarbodiimide (DCC; 0.81 g, 3.92 mmol) was added in one portion to a rapidly-stirred mixture of 4-[[[(2,6-dimethylphenyl)amino]carbonyl]methyl]-1-piperazineacetic acid (1.0 g, 3.27 mmol), 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 0.88 g, 3.27 mmol) and dimethylaminopyridine (DMAP: 40 mg) in anhydrous dimethylformamide (25 mL). After 2 hours at ambient temperature, an additional equivalent of DCC and DMAP were added. The mixture was stirred further for 22 hours at room temperature before it was heated to 70° C. for 6 hours. Upon cooling, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried and concentrated. Purification of the residue by flash chromatography on silica gel (gradient elution with 50% ethyl acetate in hexanes followed by ethyl acetate) afforded 0.50 g of the benzoin ester product (VI) as an off-white solid. The ester was used in subsequent reactions without additional purification.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:11][CH:12]([OH:23])[CH2:13][N:14]([CH2:20][CH2:21][OH:22])[CH2:15][CH:16]([OH:19])[CH2:17]Cl>C1(C)C(C)=CC=CC=1>[OH:23][CH:12]([CH2:13][N:14]([CH2:20][CH2:21][OH:22])[CH2:15][CH:16]([OH:19])[CH2:17][NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCCN(CC(O)CCl)CC(O)CCl
Reactant: CCCCCCCCN
Solvent: Cc1ccccc1C
Product: CCCCCCCCNCC(O)CN(CCO)CC(O)CNCCCCCCCC
Temperature: 70 °C
Yield: 69.1 %

Procedure:
A reactor was charged with 275 g (2.2 moles) of octylamine, and the contents were heated to 70° C. To the contents, a solution with 36 g (0.17 mole) of N,N-bis(3-chloro-2-hydroxypropyl)hydroxyethylamine dissolved in 30 g of xylene was then added dropwise over 40 minutes. The resultant mixture was aged further for 4 hours. Thereafter, xylene was distilled off under reduced pressure, and unreacted octylamine was then distilled off at 70° C. and 0.5 mmHg. A mixture of 500 ml of xylene and 500 ml of 5% aqueous sodium hydroxide was added to the residue to subject it to extraction and washing. Thereafter, a xylene layer was taken out and concentrated, thereby obtaining 50.7 g (yield: 69%) of 11,15-dihydroxy-13-hydroxyethyl-9,13,17-triazapentacosane represented by the following formula. ##STR13##
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]#[N:22])=[CH:11][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:23]O.[OH-].[Na+].O>CN1C(=O)CCC1>[C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]([NH2:22])=[O:23])=[CH:11][C:10]=3[N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: N#Cc1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4-(phenylamino)thieno[3,2-c]quinoline-7-carbonitrile (34 mg, 0.113 mmol) was dissolved in NMP (0.3 ml). 30% aqueous H2O2 (0.2 ml) was added followed by addition of 6N NaOH (50 ul). The mixture was stirred at 50° C. for 2 hours. An extra amount of 30% aqueous H2O2 (0.3 ml) and 6N NaOH (100 ul) were added and a 70% conversion was achieved after 30 min. Water was added and the solid filtered and dried. The material was further reacted under the same conditions in order to achieve a complete transformation. 4-(phenylamino)thieno[3,2-c]quinoline-7-carboxamide was isolated as solid (30 mg, 83% yield). LCMS (ES): 95% pure, m/z 320 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1)#[N:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ccn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(C#N)ccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(4-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.18 g, 3.31 mmol) in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 5 using 1 N HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (b, 1H), 9.24 (b, 1H), 8.30 (d, J=5.2 Hz, 1H), 7.57 (s, 1H), 7.50 (dd, J=5.2, 1.2 Hz, 1H), 7.17 (d, J=2 Hz, 1H), 7.01 (d, J=1.6 Hz, 1H), 5.45 (dd, J=9.6, 2 Hz, 1H), 3.02 (dd, J=15.6, 2.4 Hz, 1H), 2.46 (s, 3H), 2.08 (dd, J=16, 10 Hz, 1H). MS (ESI) m/z=323 [M−H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.[CH3:20][NH:21][O:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].CCO>O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:9](=[O:10])[NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:21]([O:22][CH3:23])[CH3:20])[N:4]=1
Reactant: CNOC
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Yield: 86 %

Procedure:
A mixture of Intermediate 4: 2-(3-(3-fluorobenzyl)ureido)-4-chloromethyl-thiazole (40 g, 0.133 mol), N,O-dimethylhydroxylamine (80 g, 0.820 mol), sodium carbonate (40 g, 0.754 mol), and abs. EtOH (0.2 L) was stirred and heated at 60-70 C for 8-12 hours. The mixture was diluted with water (0.8 L) and cooled to 20 C with continued stirring. The solids were collected by filtration, washed with water, and dried in vacuo to afford the title compound (37 g, 86% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[F:12][C:13]([F:55])([F:54])[C:14]1[CH:15]=[C:16]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:17][N:18]([C@H:31]1[CH2:35][C@@H:34]([CH2:36][O:37][CH3:38])[N:33]([C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41](Cl)[N:40]=2)[CH2:32]1)[C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:21][N:20]=1.[OH-].[Na+].Cl>C(O)(C)C>[F:52][C:50]([F:51])([F:53])[C:48]1[CH:47]=[C:16]([CH:15]=[C:14]([C:13]([F:12])([F:55])[F:54])[CH:49]=1)[CH2:17][N:18]([C:19]1[N:20]=[CH:21][C:22]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:23][N:24]=1)[C@@H:31]1[CH2:32][N:33]([C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]3)[N:40]=2)[C@H:34]([CH2:36][O:37][CH3:38])[CH2:35]1
Reactant: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(Cl)ncc1Cl
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(N2CCC(C(=O)O)CC2)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 284.6 %

Procedure:
A 5 ml test tube for microwave reactor is charged with ethyl piperidine 4-carboxylate (202 mg, 1.28 mmol), (3,5-bis-trifluoromethyl-benzyl)-[(3S,5S)-1-(2,5-dichloro-pyrimidin-4-yl)-5-methoxymethyl-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (170 mg, 0.26 mmol) and isopropanol (1.5 ml). Then, the test tube is set into microwave reactor at 95 degree for 2 hours. After cooling to rt, reaction mixture is transferred into a 25 ml round-bottom flask and solvent is removed under reduced pressure. Then, into the flask is added 1N NaOH (1.28 ml, 1.28 mmol). The mixture is stirred for 1 hour, and pH is adjusted to 6-7 using 1.5 N HCl. The resulted solution is extracted with EtOAc and the organic layer is dried over MgSO4. The solvent is removed under reduced pressure, and the obtained residue is purified with reverse phase column to give 1-[4-((2S,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-methoxymethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidine-4-carboxylic acid (78 mg, 0.74 mmol, 58% for 2 steps).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:30]#[N:31].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:30]([CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38.6 %

Procedure:
A suspension of 350 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole, prepared in step a) in Example 2, in 7 ml of DMF was cooled in ice, and 94 mg of sodium cyanide was added to the cooled suspension under an argon atmosphere. The mixture was stirred at room temperature for 2.5 hr, and brine was then added to the reaction solution. The mixture was extracted twice with ethyl acetate, and the organic layers were combined, followed by washing with brine. The washed organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 132 mg of the title compound.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH2:11].OC(COC1C2C(=CC=CC=2)C=CC=1)CN[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2>>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH:11][C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2
Reactant: NCC(O)COc1ccccc1-c1ccccc1
Reactant: OC(CNc1ncnc2[nH]cnc12)COc1cccc2ccccc12
Product: OC(CNc1ncnc2[nH]cnc12)COc1ccccc1-c1ccccc1

Procedure:
By substituting 3-[(1,1'-biphenyl)-2-yloxy]-2-hydroxypropylamine (4.88 g, 0.0174 moles) for the starting material of Example 2 and following the method of Example 2, the desired compound is obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH:40][C:41]2[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=2[F:48])=[O:33])[CH2:28][CH2:27]1.O>CS(C)=O>[F:48][C:42]1[CH:43]=[C:44]([I:47])[CH:45]=[CH:46][C:41]=1[NH:40][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][C:34]=1[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=2)[CH2:27][CH2:28]1)=[O:33]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: NC1CCN(C(=O)c2ccncc2Nc2ccc(I)cc2F)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(CC(=O)NC2CCN(C(=O)c3ccncc3Nc3ccc(I)cc3F)CC2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 109.2 %

Procedure:
A mixture of p-tolyl acetic acid (0.027 g, 0.180 mmol) and CDI (0.036 g, 0.222 mmol) in dry DMSO (2 mL) was heated to 50° C. for 2 h prior to addition of 4-[(4-aminopiperidin-1-yl)carbonyl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine hydrochloride (described above) (0.052 g, 0.109 mmol). The contents were then stirred at room temp. After 6 h, HPLC indicated near-complete reaction. The contents were poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organics were washed with brine (2×30 mL), dried over sodium sulfate and concentrated to a yellow oil. The oil was further dried under high vacuum for 2 h at 40° C. to provide the desired product as a yellow semi-solid (0.068 g, 0.119 mmol, 66%). LC/MS [8.92 min; 573 (M+1)]
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][CH2:7][CH:8]([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:9]([CH:8]1[O:16][C:29](=[O:31])[N:6]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=2)[CH2:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(CNc1ccc(Br)cc1)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OC(Cc2ccccc2)CN1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 121.6 %

Procedure:
A solution containing 1-(4-bromoanilino)-3-phenyl-2-propanol (1.90 g, 0.00621 mol), N,N-diisopropylethylamine (2.48 g, 0.0193 mol) and N,N-dimethylaminopyridine (0.152 g, 0.00124 mol) in anhydrous dichloromethane (64 mL) was cooled to 0° C. and the solution of triphosgene (0.92 g, 0.0031 mol) in anhydrous dichloromethane (16 mL) was added dropwise. The reaction mixture was slowly warmed up to ambient temperature while stirring under an atmosphere of nitrogen for 18 hours. The organic phase was washed with saturated solution of sodium bicarbonate in water (70 mL), brine (60 mL) and dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 5-benzyl-3-(4-bromophenyl)-1,3-oxazolan-2-one (1.25 g, 0.00377 mol) as a white solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[S:43][C:42]([CH:44]([CH3:46])[CH3:45])=[N:41][CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[S:43][C:42]([CH:44]([CH3:46])[CH3:45])=[N:41][CH:40]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(2-isopropyl-thiazol-5-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH3:12][N:13]([CH2:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:31][CH:30]=3)=[O:28])=[CH:22][CH:23]=2)[NH:18][CH2:17]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:14][N:13]([CH2:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([NH:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][CH:34]=3)=[O:28])=[CH:22][CH:23]=2)[N:18]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17]1)[CH3:12]
Reactant: CN(C)CC1CNc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C)CC1Cc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.02 ml) was added to pyridine solution (1 ml) of N-[3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl]-4-biphenylcarboxamide (80 mg) under ice-cooling, which was stirred at room temperature for 1 hour. Further, methanesulfonyl chloride (0.02 ml) was added to the reaction mixture under ice-cooling, which was stirred at room temperature for 12 hours. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized using THF-IPE to give the titled compound (64 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].O=S(Cl)[Cl:19].CC(=O)OCC>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([Cl:19])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (2 g, 8.51 mmol) in DCM (30 mL) was added SOCl2 (1.242 mL, 17.01 mmol) at 20° C. The mixture was stirred at 20° C. for 2 h. TLC (PE/EA=2:1, Rf=0.3) showed the reaction was finished. The mixture was concentrated to give 3-nitro-5-(trifluoromethyl)benzoyl chloride (1.8 g, 6.50 mmol, 76% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:15]1[CH2:16][CH2:17][C:12]2([O:11][C:10]3[C:20]4[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=3[S:19][CH2:18]2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=4)[CH2:13][CH2:14]1)=[O:29]
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C(=O)c4cccc(Cl)c4)CC3)O1)C(=O)C2=O

Procedure:
Compound 69 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=125-127° C.; 400 MHz 1H NMR (CDCl3) δ: LCMS: 7.90 (d, 1H), 7.55-7.47 (m, 3H), 7.41 (m, 1H), 7.25 (d, 1H), 7.11 (dd, 1H), 3.94, (s, 3H), 3.55-3.40 (m, 2H), 3.11 (s, 2H), 2.18-1.92 (m, 4H), 1.89-1.82 (m, 2H); LCMS: 470 [M+H].