Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]1>>[OH:41][CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:35][CH2:36]1
Reactant: OCC1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCC(CO)CC1
Yield: 40 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalents of 4-piperidinylmethanol as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]Br>C(OCC)C>[Br:11][C:5]1[O:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: COC(=O)c1occc1C
Solvent: CCOCC
Product: COC(=O)c1oc(Br)cc1C
Reaction time: 14 h
Yield: 85.3 %

Procedure:
To a solution of methyl 3-methylfuran-2-carboxylate (3.0 g, 21.41 mmol) in ethyl ether (100 mL) was added bromine (1.210 mL, 23.55 mmol) dropwise at RT and the mixture was allowed to stir for 14 h. Evaporation followed by purification by flash chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) yielded the title compound (4.0 g, 85% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 6.31 (s, 1H), 3.88 (s, 3H), 2.33 (s, 3H); HPLC retention time: 2.776 min, LCMS (ES): m/z 219, 221 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:13]#[C:14][NH2:15].[Na]>C(O)C>[C:14]([N:15]=[C:11]([C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)[NH2:12])#[N:13]
Reactant: N#CN
Reactant: N#Cc1cccc2ncccc12
Agent: [Na]
Solvent: CCO
Product: N#CN=C(N)c1cccc2ncccc12
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A mixture of Example 24A (750 mg, 4.81 mmol) and sodium cyanamide (312 mg, 4.81 mmol) in ethanol (10 mL) was heated at reflux for 10 hours and cooled to ambient temperature. The solvent was removed under reduced pressure and the crude mixture was purified by silica gel chromatography, eluting with a gradient of 0-6% of methanol/methylene chloride to provide 0.3 g of the title compound. MS (ESI+) m/z 197 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:34][CH3:35])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)[N:5]([C:19]([NH:21][C@H:22]([CH2:30][CH:31]=[CH2:32])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[O:20])[C:4]1=[O:33])[CH3:2].[Br-].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:57]([NH:59][CH2:60][CH3:61])[CH3:58]>>[CH2:34]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:59]([CH2:60][CH3:61])[CH2:57][CH3:58])[CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)[N:5]([C:19]([NH:21][C@H:22]([CH2:30][CH:31]=[CH2:32])[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:20])[C:4]1=[O:33])[CH3:35]
Reactant: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(O)COC)cc1)c1ccc(C)cc1
Reactant: CCNCC
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(COC)N(CC)CC)cc1)c1ccc(C)cc1

Procedure:
According to the procedure given in Example 21, Step D, 86 mg (0.18 mmol) of 3,3-diethyl-1-[(R)-α-(allyl)-4-(methyl)benzylaminocarbonyl]-4-(S)-[4-(1-(RS)-(hydroxy)-2-methoxyethyl) phenoxy]azetidin-2-one, 98 mg (0.23 mmol) of triphenylphosphine dibromide and ca. 0.3 mL of diethylamine gave after purification on 15 gm of silica eluting with 500 mL of 98:2 methylene chloride: methanol then 200 mL of 97.5:2.5 methylene chloride: methanol 44 mg (46%) of an oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([F:19])=[C:15](Cl)[N:14]=1>CO.O>[Cl:12][C:13]1[N:18]=[C:17]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([CH2:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=2)[C:16]([F:19])=[CH:15][N:14]=1
Reactant: Nc1ccc(CCCF)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: FCCCc1ccc(Nc2nc(Cl)ncc2F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(3-Fluoropropyl)aniline and 2,6-dichloro-5-fluoropyrimidine (1.5 g) were dissolved in methanol (5 mL) and water (1 mL). The reaction solution was stirred at rt for 3 d. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were evaporated and purified by flash column chromatography (EtOAc/hexanes=1/4, 1/2) to give 2-chloro-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-4-pyrimidineamine.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH:24][NH2:25]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:25][N:24]([CH3:23])[C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Reactant: CNN
Product: CCc1nn(C)c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
4-(1-Benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1-methyl-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione and methylhydrazine in analogy to Example 190 b): light yellow viscous oil; MS (ISP): 309.2 ((M+H)+.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[Br:14][C:11]1[CH:12]=[C:13]2[C:5]([C:3]3[S:17][C:16]([NH2:18])=[N:15][CH:2]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Solvent: CCO
Product: Nc1ncc(-c2c[nH]c3ncc(Br)cc23)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A mixture of 2-bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (0.5 g, 1.6 mmol), thiourea (180 mg, 2.4 mmol) in ethanol (15 ml) were stirred at 100° C. under nitrogen overnight. Solvent was removed and the crude was titurated with DCM, filtered, and washed with more DCM afforded 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (114 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.21 (s, 1H), 8.15 (s, 1H), 8.42 (s, 1H), 8.58 (s, 1H), 8.98 (s, 2H), 12.42 (s, 1H). MS: m/z 295.0 (M+H+).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:33])[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:11][C:5]=2[S:4]1.[C:34](=[O:47])([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=1)[O:35][CH2:36][CH3:37]>>[C:34](=[O:47])([O:38][C:39]1[CH:44]=[CH:43][C:42](/[CH:45]=[C:12](/[C:10]2[CH:9]=[CH:8][C:6]3[S:7][C:3]([CH3:2])([CH3:33])[S:4][C:5]=3[CH:11]=2)\[CH3:13])=[CH:41][CH:40]=1)[O:35][CH2:36][CH3:37]
Reactant: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Oc1ccc(C=O)cc1
Agent: [Br-]
Product: CCOC(=O)Oc1ccc(/C=C(\C)c2ccc3c(c2)SC(C)(C)S3)cc1

Procedure:
In analogy to Example 45, by reacting [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide with ethyl 4-formylphenyl carbonate, there was obtained ethyl p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenyl carbonate, melting point 93°-94° C. Hydrolysis of this compound with aqueous potassium hydroxide in ethanol gave p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenol, melting point 123°-124° C.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:17][CH:2]([F:1])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[C:4]=1[CH3:16]
Reactant: C1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)F
Product: Cc1c(-c2ccc(C(=O)N3CCCCC3)s2)noc1C(F)F
Yield: 66 %

Procedure:
Prepared from 5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid (Preparative Example 26) and piperdine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, then chromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid (54 mg, 66%). 1H NMR (CDCl3) 1.65-1.72 (6, 3 H), 2.34 (s, 3 H), 3.67-3.70 (m, 4 H), 6.80 (t, J=53.2, 1 H), 7.30 (d, J=4.0, 1 H), 7.43 (d, J=3.5, 1 H).13C NMR 7.7, 24.7, 26.3, ˜46 (br), 39.8 (br), 108.1 (t, J=238), 113.5, 127.6, 128.9, 131.6, 140.1, 157.8, 159.5 (q, J=29), 162.7. 19F NMR −118.2 (J=53.5). LC/MS 6.18 min, [M+1]+ 327.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.[F:66][C:67]1([F:122])[C:79]2[CH:78]=[C:77]([C:80]3[CH:81]=[CH:82][C:83]4[N:87]=[C:86]([C@@H:88]5[CH2:96][C:91]6([O:95][CH2:94][CH2:93][O:92]6)[CH2:90][N:89]5[C:97](=[O:110])[C@@H:98]([NH:105][C:106](=[O:109])[O:107][CH3:108])[CH:99]5[CH2:104][CH2:103][O:102][CH2:101][CH2:100]5)[NH:85][C:84]=4[CH:111]=3)[CH:76]=[CH:75][C:74]=2[C:73]2[C:68]1=[CH:69][C:70]([C:112]1[NH:116][C:115]([C@@H:117]3[CH2:121][CH2:120][CH2:119][NH:118]3)=[N:114][CH:113]=1)=[CH:71][CH:72]=2.Cl>>[CH3:108][O:107][C:106](=[O:109])[NH:105][C@@H:98]([CH:99]1[CH2:104][CH2:103][O:102][CH2:101][CH2:100]1)[C:97]([N:89]1[C@H:88]([C:86]2[NH:85][C:84]3[CH:111]=[C:80]([C:77]4[CH:76]=[CH:75][C:74]5[C:73]6[C:68](=[CH:69][C:70]([C:112]7[NH:116][C:115]([C@@H:117]8[CH2:121][CH2:120][CH2:119][N:118]8[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]8[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=8)=[N:114][CH:113]=7)=[CH:71][CH:72]=6)[C:67]([F:66])([F:122])[C:79]=5[CH:78]=4)[CH:81]=[CH:82][C:83]=3[N:87]=2)[CH2:96][C:91]2([O:95][CH2:94][CH2:93][O:92]2)[CH2:90]1)=[O:110]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1nc3ccc(-c4ccc5c(c4)C(F)(F)c4cc(-c6cnc([C@@H]7CCCN7)[nH]6)ccc4-5)cc3[nH]1)OCCO2)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1nc3ccc(-c4ccc5c(c4)C(F)(F)c4cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc4-5)cc3[nH]1)OCCO2)C1CCOCC1

Procedure:
Title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-8-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3× HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 972.54 [M+H]+. (30 mg, 43%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]=1[CH:14]=[O:15]>CO.C1COCC1>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]=1[CH2:14][OH:15]
Reactant: O=CC1=C(Cl)c2ccccc2CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC1=C(Cl)c2ccccc2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To a mixture of sodium borohydride (2.83 g, 0.075 mol) in methanol (150 mL) at 0° C., was added dropwise a solution of 1-chloro-2-formyl-3,4-dihydronaphthalene (9.59 g, 0.05 mol) in dry THF (150 mL). The reaction was stirred at room temperature for 1 hour, carbon dioxide was cautiously bubbled through the reaction mixture for 15 minutes, and the resulting mixture was concentrated under reduced pressure. The residue was diluted with water (150 mL), extracted with ether (3×150 mL), dried (MgSO4) and concentrated to give 9.95 g (102%) of product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=1.C(N(CC)CC)C>C(O)C>[CH3:38][S:37][C:33]1[N:34]=[C:35]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:31][N:32]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSc1nccc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)n1
Yield: 26.8 %

Procedure:
A mixture of 1.50 g (0.0037 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine [U.S. Pat. No. 4,025,629], 0.44 ml (0.00375 mol) of 4-chloro-2-methylthiopyrimidine, 0.52 ml (0.00375 mol) of triethylamine, and 125 ml of ethanol is stirred at reflux for 3 hours. After cooling, the ethanol is removed in vacuo and the residue is stirred with methylene chloride and aqueous sodium bicarbonate. The resultant solid is collected and washed with water and ether. Crystallization from methanol-chloroform gives 0.52 g (26%) of 1-[2-(methylthio)-4-pyrimidinyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, of melting point 166°-267° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH:26][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccc(F)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc(F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Suspend 5-(4-formylphenoxy)pyridine-2-carboxamide (0.0271 g, 0.112 mmol) In methanol (2.1 mL). Add 4-fluorophenethylamine (0.015 mL, 0.112 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (in small excess) and stir for additional 3 hours. Load the reaction mixture directly onto a 5 g SCX column. Wash the column with methanol and elute with 2.0 M NH3 in methanol. Purify by flash chromatography, eluting with 70% ethyl acetate, 5% (2.0 M NH3 in methanol) and 25% hexanes to give the title compound (0.0370 g, 90.5%): TOF MS ES+ 366.2 (M+H)+, base peak TOF MS ES+ 227.1 (M-NHCH2CH2C6H4F)+, HRMS calcd for C21H21N3O2F 366.1618 (M+H)+, found 366.1621, time 0.42 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95°/over 19 min], tR=10.2 min, 100% purity.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>[Cu].CS(C)=O>[F:16][C:10]([F:17])([C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Fc1cnc(Br)nc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ncc(F)cn1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
To 2-bromo-5-fluoropyrimidine (500 mg, 2.8 mmol) were added DMSO (1.5 mL), ethyl 2-bromo-2,2-difluoroacetate (0.4 mL, 3.1 mmol), and copper powder (390 mg, 6.16 mmol). The reaction vessel was sealed, and then evacuated and flushed with argon (2×). The mixture was heated at 50° C. overnight, then diluted with EtOH and filtered through Celite washing with EtOAc. To the filtrate was added water and the mixture was filtered through Celite again. The separated organic layer was washed with brine (2×), dried over sodium sulfate, and concentrated to afford ethyl 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate as an oil (470 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 2H), 4.41 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Cl:22])[CH2:5][CH:6]([CH3:21])[C:7]1[C:15]2([CH3:16])[CH:10]([CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:18]([O:17][CH:11]1[CH:10]2[C:15]([CH3:16])([C:7]([CH:6]([CH3:21])[CH2:5][CH:4]([Cl:22])[CH2:3][OH:2])=[CH:8][CH2:9]2)[CH2:14][CH2:13][CH2:12]1)(=[O:20])[CH3:19]
Reactant: COC(=O)C(Cl)CC(C)C1=CCC2C(OC(C)=O)CCCC12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)OC1CCCC2(C)C(C(C)CC(Cl)CO)=CCC12
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 1.01 g (2.95 mmol) of [3aS-[3(αS*,γR*),3aα,7β,7aβ]-7-(acetyloxy)-α-chloro-3a,4,5,6,7,7a-hexahydro-γ,3a-dimethyl-1H-indene-3-butanoic acid methyl ester in 25 mL of anhydrous tetrahydrofuran was cooled at 0° C. and treated under argon with 1.47 mL (1.47 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. After stirring for 2 hours at 0° C., additional 0.20 mL of lithium aluminum hydride solution was added and the reaction allowed to proceed for 1 additional hour. It was then quenched by careful addition of 8 mL of a 2N aqueous Rochelle salt solution, then 0.5 mL of 2N hydrochloric acid. After dilution with water, it was extracted with ethyl acetate. The combined extracts were washed with 2N aqueous Rochelle salt solution, then brine, dried and evaporated to dryness to give 0.90 g (93% yield) of the title compound as a colorless, thick oil: [α]23D-30.1° (c 0.6, EtOH); 1H NMR (200 MHz, CDCl3) δ0.93 (s, 3H), 1.07 (d, J=7.2 Hz, 3H), 2.04 (s, 3H), 2.52 (br m, 1H), 3.73 (m, 2H), 4.00 (m, 1H), 4.97 (td, J=12.0, 4.4 Hz, 1H), 5.27 (br s, 1H) ppm.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH3:27])=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23]C)=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[CH3:27])=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1-c1ccc(C(=O)O)nc1)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.47 mL, 1.42 mmol) was added to a THF (2 mL) and MeOH (1 mL) solution of methyl 5-(5-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)(methyl)amino)methyl)phenyl)picolinate (226 mg, 0.47 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>O>[O:16]=[C:17]1[CH:22]=[CH:21][N:20]([C:2]2[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=2)[CH:19]=[CH:18]1
Reactant: Oc1ccncc1
Reactant: CC(CC(=O)O)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)C(=O)c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A solution of 3-(4-fluorobenzoyl)butanoic acid (8 g), 4-hydroxypyridine (8 g) and sodium hydroxide (4.6 g) in water (80 ml) was heated in an autoclave at 140° C. for 20 hours. The reaction mixture was cooled and on acidification to pH3 with dilute hydrochloric acid afforded as a white crystalline precipitate 3-[4-(4-oxo -1,4-dihydropyridin-1-yl)benzoyl]butanoic acid, 9.45 g, m.p. 250-252° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[N:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc2nccc(Cl)c2c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc2nccc(-c3ccncc3)c2c1
Yield: 95.8 %

Procedure:
A mixture of 4-chloro-6-quinolinecarbonitrile (8.7 g, 46.2 mmol), 4-pyridineboronic acid (8.52 g, 69.3 mmol), tetrakis(triphenylphosphine)palladium(0) (2.67 g, 2.31 mmol) and 2 M potassium carbonate (69.3 mL, 3 eq) in 1,4-dioxane (380 mL) is heated at reflux for 3.5 hours. The dioxane is evaporated and the crude product purified by silica gel chromatography eluting with methylene chloride/methanol 0-4%. A yield of 10.23 g (95%) of the title compounds was obtained.
Reaction SMILES: [C:1]([C:6]1[CH:39]=[C:38]([C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:7]=1[O:8][CH:9]([CH2:34][CH3:35])[C:10]([N:12]1[C:17]2[CH:18]=[C:19]([O:25]CC3C=CC=CC=3)[C:20]([N+:22]([O-])=O)=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:33])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([C:6]1[CH:39]=[C:38]([C:40]([CH2:43][CH3:44])([CH3:41])[CH3:42])[CH:37]=[CH:36][C:7]=1[O:8][CH:9]([CH2:34][CH3:35])[C:10]([N:12]1[C:17]2[CH:18]=[C:19]([OH:25])[C:20]([NH2:22])=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:33])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)N1C(=O)COc2cc([N+](=O)[O-])c(OCc3ccccc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)N1C(=O)COc2cc(N)c(O)cc21

Procedure:
The nitro compound ((f), 8.19 g, 0.0136 mole) in THF (ml 100) was reduced and debenzylated under 25 PSI hydrogen pressure at room temperature in the presence of 10% Pd on charcoal. The resulting amine (g) was not isolated.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:14][N:13]3[CH:24]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:26]1C=CC2N(C(C3C=CC=CN=3)=C(C(NC3C=CC=CC=3)=O)N=2)C=1C>>[CH3:26][C:14]1[N:13]2[CH:24]=[C:10]([C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[N:11]=[C:12]2[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(I)ccc2nc(C(=O)Nc3ccccc3)c(-c3ccccn3)n12
Reactant: O=C(Nc1ccccc1)c1cn2cc(-c3ccccn3)ccc2n1
Product: Cc1c(-c2ccccn2)ccc2nc(C(=O)Nc3ccccc3)cn12

Procedure:
This product is obtained in a manner similar to that for the product of Example 3, replacing the 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide with 6-iodo-5-methyl-N-phenyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide.