Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][OH:29]>CCCCCC.C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cnc(OCc3ccc(Cl)c(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 3,4-dichlorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(3,4-dichlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC). HPLC/MS: m/e=511 (M+); Rt=5.07 min; 1H-NMR 500 MHz (CDCl3): δ 5.47 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.21 (d, J=9 Hz,1H), 7.22-7.30 (m, 3H), 7.38 (m, 2H), 7.43 (d, J=9 Hz, 1H), 7.66 (d, J=2 Hz,1H), 8.61 (s, 1H). 2-(3,4-Dichlorobenzyloxy)-4-(2-chloro-4-thiomethyl-phenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf product which was the by-product of the thiomethyl anion displacement of the 4-chloro substituent on the 4-(2,4-dichlorophenyl) ring. HPLC/MS: m/e=523 (M+1); Rt=4.93 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.48 (s, 2H), 7.0-7.10 (m, 1H), 7.15-7.21 (m, 2H), 7.24-7.30 (m, 3H), 7.40-7.60 (m, 3H), 7.68 (d, J=2 Hz,1H), 860 (s, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])[CH3:6].NC1C([N+]([O-])=O)=C(C)C([N+]([O-])=O)=CC=1C#N>>[C:5]([NH:8][C:9]1[C:10]([N+:1]([O-:4])=[O:2])=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1C
Agent: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Product: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (100 mL, 2.4 mol) is cooled to about 0° C. (ice/acetone/water bath) and 3-(Acetylamino)-4-methylbenzoic Acid (14) (24.567 g, 127.2 mmol) is added in small portions over about 30 minutes, at rate to maintain the internal reaction temperature <5° C. The hetereogeneous reaction mixture is then stirred at about 0° C. for an additional 1 hour. The reaction mixture is then added to ice water (300 mL) and stirred for about 1 hour. The solid obtained is filtered and dried to provide a mixture of 3-N-acetyl-4-methyl-2-nitro benzoic acid (5) and 3-N-acetyl-4-methyl-5-nitro benzoic acid, in ratio of about 78:22 (27.79 g, 92% Combined Yield). A portion of this mixture (23.458 g) is recrystallized from acetic acid (300 mL) to give 3-(Acetylamino)-4-methyl-2-nitrobenzoic Acid (15), as a white solid (15.370 g, 51% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=2)=[O:21])=[CH:5][CH:4]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:24]([F:29])[CH:23]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)c(F)c2)cc1

Procedure:
900 mg (2.20 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][3-fluoro-4-hydroxyphenyl]methanone was dissolved in 12 mL of DMF and 810 mg (4.4 mmol) of 1-(2-chloroethyl)piperidine hydrochloride was added. To the reaction mixture was added 3.3 g (10 mmol) of Cs2CO3 and heated to reflux for one hour. The reaction mixture was filtered to remove the solids. The solvents were removed by evaporation and the residue was chromatographed on a silica gel column eluted with a linear gradient of beginning with CHCl3 and ending with MeOH-CHCl3 (1:19). The desired fractions were determined by tlc, combined, and evaporated to a solid. This yielded 960 mg of the title compound as a tan amorphous solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([C:13]1[CH:14]=[C:15]([F:42])[C:16]([CH3:41])=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([C:28]4[CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH:33]=4)=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH:18]=1)=[O:12])[CH3:9]>ClCCl>[CH2:8]([NH:10][C:11](=[O:12])[C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([C:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=4)=[N:24][NH:25]3)=[CH:21][CH:20]=2)[C:16]([CH3:41])=[C:15]([F:42])[CH:14]=1)[CH3:9]
Reactant: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4=CCNCC4)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2908.5 %

Procedure:
Trifluoroacetic acid (2.73 ml) was added dropwise to a solution of 1,1-dimethylethyl 4-(6-{5-[(ethylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-3-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (Intermediate 20, 50 mg) in dichloromethane (10 ml) at room temperature under nitrogen then stirred at room temperature for 1 h. More trifluoroacetic acid (1.73 ml) was added and the mixture was stirred at room temperature under nitrogen for a further 1 h. The solvent was removed and the residue was dissolved in methanol and applied to an SCX ion exchange cartridge. Elution with a solution of ammonia (0.88) in methanol gave the title compound as a white solid (1.15 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([C:26]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)=[CH:24][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN(C)c1ccc(C=O)cc1
Product: CN(C)c1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)ccnc3[nH]2)cc1
Yield: 33.3 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-(dimethylamino)benzaldehyde (31.6 mg, 0.212 mmol) were reacted to produce 25 mg (33%) of the title compound. mp: 245-251° C., 1H NMR (300 MHz, DMSO-d6): 12.73 (s, 1H), 7.96 (d, J=8 Hz, 2H), 7.84 (d, J=4 Hz, 1H), 7.65 (s, 1H), 7.15 (s, 1H), 6.81 (d, J=8 Hz, 2H), 6.70 (d, J=8 Hz, 1H), 6.37 (d, J=8 Hz, 1H), 6.32 (s, 2H), 3.89 (br s, 1H), 2.99 (s, 6H), 2.87 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=7 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 389 (M+H), HPLC: 1.97 min (G method).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:3]([C:16]2[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 48 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-tolylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-methylphenyl)-1H-indole-3-carboxaldehyde (48% yield) as a cream solid. ESI/MS 270 (M+H), 311 [(M+1+CH3CN) adduct]: RT 3.55 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:28][CH3:29])(=[O:27])/[CH:21]=[CH:22]\[C:23]([O:25][CH3:26])=[O:24].C1C=CC=CC=1.[C:36]([O:40][C:41](=[O:53])[C:42]1[CH:47]=[CH:46][C:45]([CH:48]=O)=[C:44]([N+:50]([O-:52])=[O:51])[CH:43]=1)([CH3:39])([CH3:38])[CH3:37]>C(O)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:26][O:25][C:23](=[O:24])[C:22](=[CH:48][C:45]1[CH:46]=[CH:47][C:42]([C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:53])=[CH:43][C:44]=1[N+:50]([O-:52])=[O:51])[CH2:21][C:20]([O:28][CH3:29])=[O:27]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: COC(=O)/C=C\C(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)CC(=Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC
Temperature: 25 °C
Yield: 86.6 %

Procedure:
Triphenylphosphine (13.3 g, 50.7 mmol) and dimethyl maleate (7.31 g, 50.7 mmol) were combined in glacial acetic acid (62 mL) at 25° C. and stirred for 6 h whereupon benzene (164 mL) and 4-formyl-3-nitro-benzoic acid tert-butyl ester (8.5 g, 33.8 mmol) was added. The dark solution was heated at reflux for 18 h then cooled to 25° C. Concentration in vacuo gave a dark oil. Flash chromatography (silica gel, hexane/ethyl acetate) affords the title compound as an amber oil (11.1 g, 87%). NMR (dmso-d6, 300 MHz) : δ1.6 (s, 9H, tert-butyl), 3.3 (s, 2H, CH2), 3.6 (s, 3H, CH3), 3.8 (s, 3H, CH3), 7.5-8.6 (m, 4H, ArH, ArCH).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:5][CH:6]([CH2:41][CH3:42])[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1)[CH3:4]>O1CCCC1>[CH2:3]([NH:5][CH:6]([CH2:41][CH3:42])[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1)[CH3:4]
Reactant: CCNC(CC)CCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNC(CC)CCOc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 89.6 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 250 mg (6.25 mmol) of sodium hydroxide with 340 mg (0.63 mmol) of ethyl 4′-(3-ethylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 21 b) in 30 ml of tetrahydrofuran. 290 mg of 4′-(3-ethylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=195° C., yield=90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:128])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][O:99][CH2:100][CH2:101][O:102][CH2:103][CH2:104][O:105][CH2:106][CH2:107][O:108][CH2:109][CH2:110][O:111][CH2:112][CH2:113][O:114][CH2:115][CH2:116][O:117][CH2:118][CH2:119][O:120][CH2:121][CH2:122][O:123][CH3:124])[C:5](=[O:125])[C:4]([CH3:127])([CH3:126])[NH:3]1.C(O[Cl:134])(C)(C)C>CO>[Cl:134][N:3]1[C:4]([CH3:127])([CH3:126])[C:5](=[O:125])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][O:99][CH2:100][CH2:101][O:102][CH2:103][CH2:104][O:105][CH2:106][CH2:107][O:108][CH2:109][CH2:110][O:111][CH2:112][CH2:113][O:114][CH2:115][CH2:116][O:117][CH2:118][CH2:119][O:120][CH2:121][CH2:122][O:123][CH3:124])[C:2]1([CH3:128])[CH3:1]
Reactant: CC(C)(C)OCl
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)C(C)(C)NC1(C)C
Solvent: CO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a 0° C. solution of 2,2,5,5-tetramethyl-3-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98,101,104,107,110,113,116-nonatriacontaoxaoctadecahectan-118-yl)imidazolidin-4-one (1.42 g, 0.7 mmol) in methanol (150 ml) was added tert-butylhypochlorite (209 mg, 1.9 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo, and crude material is purified by silica gel flash chromatography (0 to 10% methanol in dichloromethane) to give 775 mg (54%) of the title compound. 1H NMR (400 MHz, D2O) δ 3.72 (s, 152H), 3.65 (m, 2H), 3.58 (t, J=7.5 Hz, 2H), 3.40 (s, 3H), 1.55 (s, 6H), 1.38 (s, 6H). 13C NMR (100 MHz, D2O) δ 174.9, 83.6, 71.0, 69.5 (large peak) 67.7, 66.0, 58.1, 40.2, 24.2, 22.7.
Reaction SMILES: C1(OB(O)O)C=CC=CC=1.[F-].[K+].C(OC(C1N=C2C=CC(Br)=CN2C=1)=O)C.C([O:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][N:36]2[CH:47]=1)=[O:32])C.[OH-].[Na+].C1(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=CC=1.Cl>C(#N)C.C(O)C.[Pd].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>[C:41]1([CH:38]2[CH2:37][N:36]3[CH:47]=[C:33]([C:31]([OH:32])=[O:30])[N:34]=[C:35]3[CH2:40][CH2:39]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)c1cn2cc(-c3ccccc3)ccc2n1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)c1cn2cc(Br)ccc2n1
Solvent: CCO
Solvent: CC#N
Product: O=C(O)c1cn2c(n1)CCC(c1ccccc1)C2
Temperature: 25 °C

Procedure:
Phenylboric acid (2.13 g; 17.5 mmol) followed by KF solution (2M in water, 15 ml) and finally Pd(PPh3)4 (607 mg; 0.5 mmol; 3 mol %) were added under a nitrogen atmosphere to a solution of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (4.71 g; 17.5 mmol) in acetonitrile (30 ml) in a Milestone 100 ml high-pressure vessel. The reaction vessel was rinsed with nitrogen, closed and irradiated in a microwave at 160° C. for 5 min. (DC control: n-hexane-ethyl acetate 1:1). Two batches of the same size were run in parallel and combined prior to processing. The precipitated product was filtered out and washed with diethyl ether. The black crystalline product was taken up in chloroform and filtered first over silica gel and then over celite. The clear filtrate was concentrated to dryness. Yield: 9.3 g (100%). Stage 2. The 6-phenylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (9.32 g, 17.5 mmol) was dissolved in ethanol (80 ml) and NaOH solution (20% in water, 7 ml) was added. The reaction batch was refluxed for 8 hours. On completion of the reaction the solvent was removed in a rotary evaporator and the residue taken up in a small amount of water. The solution was carefully adjusted to pH 3-4 with HCl solution (10% in water). The precipitated product was filtered and washed with water and used in the next stage without further purification. Yield: 7.90 g (95%). Stage 3. Palladium on activated carbon (1.5 g) was added to a solution of 6-phenylimidazo[1,2-a]pyridine-2-carboxylic acid (6.3 g; 26.4 mmol) in a blend of HCl (4% in water, 100 ml) and ethanol (200 ml). The mixture was poured into an autoclave (stainless steel), the autoclave was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred over the weekend at room temperature. The catalyst was filtered out over celite and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile. Yield: 4.1 g (56%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[S:24]([NH2:28])([NH2:27])(=[O:26])=[O:25]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([NH:27][S:24]([NH2:28])(=[O:26])=[O:25])=[O:6]
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)NS(N)(=O)=O)cc2Br)ccc1O
Yield: 73.1 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with sulfamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 13 mg (73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:16])[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:11][O:12][C:13](=[O:16])[CH2:14][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cl)cc1C=O
Temperature: 80 °C

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (30 g, 192 mmol), bromo-acetic acid methyl ester (29.4 g, 192 mmol), K2CO3 (53 g, 384 mmol) and KI (9.6 g, 57 mmol) were mixed in acetone (100 mL). Then the mixture was heated at 80° C. for 30 min. The mixture was filtered and the filterate was concentrated. The residue was dissolve in ethyl acetate and washed with base aqueous solution (1N NaOH). The organic layer was separated, dried and concentrated to give (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester yellow solid. (44 g)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15].O>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN(C)CCN
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (2.0 g, 7.6 mmol, 1.0 eq) and N,N-dimethyl ethane-1,2-diamine (1.0 g, 11.5 mmol, 1.5 eq) in dioxane (20 mL) was stirred at room temperature for 2 h. Water was added and the reaction was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography to afford 5-bromo-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (1.35 g, 94%). LC-MS (m/z)=313.0, 315.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.Cl>C(#N)C>[ClH:24].[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:32](=[O:33])[NH:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@@H:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O[C@@H](CN1CCOC(c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Agent: Cl
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCO[C@@H](c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
(S)-1,1,1-Trifluoro-3-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-propan-2-ol (52 mg, 151 μmol) and 1-chloro-4-isocyanatobenzene (25.6 mg, 167 μmol) were combined in acetonitrile (2 mL). The mixture was stirred at room temperature overnight and evaporated. The residue was purified by flash chromatography (20% EtOAc/hexanes) to provide the later-running isomer, which was converted to the HCl salt to afford (4-chloro-phenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(S)-2-(4-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride as a white solid (30 mg). (M+H)+=497 m/e.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[O:16].[OH-].[Na+]>C(O)C>[OH:16][CH2:15][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: C=O
Reactant: CC(C)(C)C(=O)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(=O)C(CO)Oc1ccccc1
Yield: 65.2 %

Procedure:
1Phenoxy-3,3-dimethyl-butan-2-one (192.2 g, 1.0 mol) prepared according to German Offenlegungsschrift, i.e., (German Published Specification No. 2,105,490; Example 3) and having a boiling point of 75°-83°C at 0.08 atmospheres is dissolved in ethanol (800 ml) and a 30% formaldehyde solution (240 ml, 2.4 mols) is added. A 10% sodium hydroxide solution (5 ml) is then added until the pH is 9. The reaction mixture is heated for 4 hours reflux and the solvent is distilled off in vacuo. The resulting precipitate is filtered off, well rinsed with petroleum ether and discarded. The filtrate is freed from the solvent in vacuo and the resulting oil is taken up in ether and extracted by shaking with water. The organic phase is dried over sodium sulphate and freed from the solvent and the residue is purified by vaccum distillation to afford 145 g (65% of theory) of 1 -hydroxy-2-phenoxy-4,4-dimethyl-pentan-3-one, boiling point 95°-100°C (0.1 mm Hg).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:5][CH:4]([CH:6]([NH:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.O.CO>[CH3:1][C:2]1([CH3:34])[CH2:5][CH:4]([CH:6]([NH:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3ccccc3c2)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(C(Nc2cnc3ccccc3c2)c2ccc(C(=O)NCCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.2 %

Procedure:
To a flask containing ethyl 3-(4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzamido)propanoate (11.9 mg, 0.0650 mmol) was added tetrahydrofuran (0.0650 mL), methanol (0.0650 mL), and 1 N sodium hydroxide (0.0650 mL, 0.0650 mmol). The reaction was stirred for 18 h at room temperature. The reaction was then diluted with ethyl acetate and water. 1 N hydrochloric acid (0.0650 mL) was then added dropwise to bring the pH to 3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to provide 3-(4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzamido)propanoic acid (9.3 mg, 83% yield) as a solid. 1H NMR (400 MHz, CD3OD) δ: 8.50 (d, J=2.7 Hz, 1H), 8.45 (t, J=5.8 Hz, 1H), 7.81-7.70 (m, 3H), 7.61-7.52 (m, 2H), 7.52-7.41 (m, 1H), 7.41-7.21 (m, 2H), 6.93 (d, J=2.7 Hz, 1H), 4.39 (d, J=9.8 Hz, 1H), 3.69-3.55 (m, 2H), 2.71-2.51 (m, 3H), 2.11 (ddd, J=11.4, 7.8, 4.1 Hz, 1H), 1.85-1.70 (m, 2H), 1.57 (ddd, J=11.3, 7.8, 4.1 Hz, 1H), 1.18 (s, 3H), 1.13 (s, 3H). MS (M+1): 432.3.