Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)([CH3:5])([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)Cl
Reactant: Clc1ccccc1
Agent: Cl
Product: CC(C)(C)c1ccc(Cl)cc1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
To 169 g of chlorobenzene was added 1.5 g of ferric chloride, and hydrogen chloride gas was blown into the mixture for 10 minutes. Then, 46 g of tert-butyl chloride was added dropwise to the mixture at 30° C. over a period of 1 hour. The mixture was maintained at 30° C. for 2 hours. The reaction mixture was washed with an aqueous solution of sodium carbonate and then with water, and evaporated under reduced pressure to give 25 g of 4-tert-butylchlorobenzene (bp.: 113° C./28 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O[C@@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.32 mmol), (3S,4R)-pyrrolidine-3,4-diol (170 mg, 1.65 mmol) and TEA (369 μL, 2.64 mmol) in DMSO (1322 μL) was stirred at 90° C. for 20 h. The RM was treated with 0.5 M HCl (15 mL) and extracted with EtOAc (30 mL). The aq. phase was back-extracted with EtOAc (2×20 mL) and the combined organic layers were washed with sat. NaHCO3 and brine, and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=461.2-463.1 [M+H]+, m/z=459.1-461.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.40 (dd, J=9.90, 4.52 Hz, 2H) 3.67 (dd, J=9.66, 5.26 Hz, 2H) 4.06-4.16 (m, 2H) 4.94 (d, J=4.65 Hz, 2H) 6.86 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.80-7.91 (m, 3H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[C:33]([F:34])=[CH:32][C:31]([C:35]([F:38])([F:36])[F:37])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine in dimethylsulfoxide at 100° C. in the presence of potassium carbonate. LC (method 4): tR=1.21 min; Mass spectrum (ESI+): m/z=541 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:10]2[CH:11]=[N:12]C=[N:14][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.NN.O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:10]2[CH:11]=[N:12][NH:14][CH:15]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cncnc1
Agent: NN
Solvent: CCO
Solvent: O
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cn[nH]c1

Procedure:
The methiodide salt of α,α-bis(4-chlorophenyl)-pyrimidine-5-methanol (12.8 g) was heated to reflux with 3 g of anhydrous hydrazine in ethanol. The original slurry went into solution and then a precipitate formed, at which time 25 ml of water were added. The mixture was heated at reflux for 20 minutes, filtered hot, water was added and the mixture was extracted with ether. The ether was evaporated and the residue was crystallized from chloroform to provide the title product, m.p. 135°-137° C. The NMR and mass spectra were consistent with the desired structure.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][CH:19]=[C:18]1[C:13]=2[CH:14]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15][CH2:16][CH2:17]1)C1C=CC=CC=1>CCO.[Pd]>[Si:24]([O:23][CH:14]1[C:13]2[C:18](=[CH:19][N:20]=[C:21]3[C:12]=2[CH:11]=[CH:10][C:9]([OH:8])=[CH:22]3)[CH2:17][CH2:16][CH2:15]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(O)ccc3c21
Yield: 89.1 %

Procedure:
A solution of Compound 225 (2.00 g, 4.77 mmol) in EtOH (80 mL) was hydrogenated over 10 percent Pd/C (1.00 g) under hydrogen atmosphere (ambient pressure) for four hours. The catalyst was removed by filtration through Celite with elution by 50 percent Et3N in THF (1.5 L). The combined filtrate was evaporated in vacuo to provide Compound 141a (1.40 g, 89 percent): white crystalline solid; mp 248°-250° C. (dec., from MeOH--Et3N); Rf =0.48 (silica, 3.2 percent methanol in dichloromethane); IR (KBr) νmax 3400, 2929, 2857, 1622, 1619, 1611, 1477, 1404, 1249, 1238, 1212, 1088, 1034, 838, 773 cm-1 ; 1H NMR (300 MHz, CDCl3) δ9.99 (br s, 1 H, ArOH), 8.52 (s, 1 H, H6), 7.91 (d, J=9.0 Hz, 1 H, H1), 7.20 (d, J=2.4 Hz, 1 H, H4), 7.14 (dd, J=9.0, 2.4 Hz, 1 H, H2), 5.43 s, 1 H, H10), 2.95-2.84 (m, 1 H, H7), 2.79-2.65 (m, 1 H, H7), 2.14-2.04 (m, 1 H, H8 or H9), 2.00-1.87 (m, 1 H, H8 or H9), 1.86-1.65 (m, 2 H, H8 or H9), 0.79 (s, 9 H, SiC(CH3), 0.00 (s, 3 H, SiCH3), - 0.02 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 330 (M+H, 100), 272 (14), 198 (9); HRMS for C19H28NO2Si (M+H), calcd 330.1889, found 330.1890. Anal Calcd for C19H27NO2Si: C, 69.26; H, 8.26; N, 4.25. Found: C, 69.10; H, 8.17; N, 4.16.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12](Cl)=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[CH3:34][O:35]C1C=C2C(C=C(OS(C(F)(F)F)(=O)=O)N=C2)=CC=1>>[ClH:4].[ClH:1].[ClH:4].[CH3:34][O:35][C:13]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:16]3[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:26]=4)[CH:21]=3)[N:9]=[CH:10]2)=[CH:5][CH:14]=1
Reactant: COc1ccc2cc(OS(=O)(=O)C(F)(F)F)ncc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Product: COc1ccc2cc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)ncc2c1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 7-methoxyisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.32-2.44 (m, 4H), 3.23-3.31 (m, 2H), 3.58-3.67 (m, 2H), 4.08 (s, 3H), 4.61-4.72 (m, 1H), 7.67-7.74 (m, 2H), 8.08 (s, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.65 (s, 1H), 8.79 (d, J=2.0 Hz, 1H), 9.51 (s, 1H). MS (ES+): m/z=401.14 [MH+]. HPLC: tR=1.88 min (ZQ3, polar—5 min).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([O:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:24]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=3)[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C>>[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=3)[CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3cccc(O)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(O)c2)cc1Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-((3-hydroxyphenyl)amino)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, hexane and diisopropyl ether were added to the obtained residue, and solid matter was filtrated to give 4-(3-hydroxyphenyl)-2-((3-hydroxyphenyl)amino)benzoic acid 10 mg of a yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26](O)=[O:27])=[CH:23][CH:24]=3)[CH:19]=[N:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:41][CH2:42][CH:43]([NH:48][S:49]([C:52]1[C:57]([CH3:58])=[CH:56][C:55]([O:59][CH2:60][CH2:61][CH2:62][C:63](=[O:89])[NH:64][CH2:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][CH2:77][NH:78][C:79]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:80])=[CH:54][C:53]=1[CH3:90])(=[O:51])=[O:50])[C:44]([O:46][CH3:47])=[O:45].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:58][C:57]1[CH:56]=[C:55]([O:59][CH2:60][CH2:61][CH2:62][C:63](=[O:89])[NH:64][CH2:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][CH2:77][NH:78][C:79]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:80])[CH:54]=[C:53]([CH3:90])[C:52]=1[S:49]([NH:48][CH:43]([CH2:42][NH:41][C:26]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:9]1[N:8]([C:7]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=[CH:11][N:10]=1)[N:18]=[CH:19]2)=[O:27])[C:44]([O:46][CH3:47])=[O:45])(=[O:51])=[O:50]
Reactant: COC(=O)C(CN)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCCOCCOCCOCCCNC(=O)OCc2ccccc2)cc1C
Reactant: O=C(O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CNC(=O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCCOCCOCCOCCCNC(=O)OCc2ccccc2)cc1C

Procedure:
A solution of 1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxylic acid, methyl 3-amino-2-(((2,6-dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)propanoate, DIEA, and HBTU in anhydrous DMF are stirred at ambient temperatures under nitrogen for 4 h. The DMF is removed under vacuum and the resulting residue is dissolved in EtOAc and washed with water, saturated NaHCO3, and saturated NaCl. The EtOAc layer is dried (MgSO4) and concentrated to dryness. The crude product is purified by flash chromatography on silica gel using EtOAc/MeOH.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH2:20]([O:24][C:25]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)[CH:21]([CH3:23])[CH3:22].[O-]CC.[Na+]>>[CH2:20]([O:24][C:25]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=1/[CH:27]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: COc1cccc(C=O)c1OCC(C)C
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: CC[O-]
Agent: [Na+]
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C#N)cc2)c1OCC(C)C
Yield: 44.5 %

Procedure:
The title compound was prepared by the reaction of Intermediate 4 (350 mg, 1.325 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (409 mg, 1.961 mmol) in presence of sodium ethoxide (178 mg, 2.264 mmol) according to the procedure described in Example 9 to give 270 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.85 (d, J=3.9 Hz, 4H), 2.03 (d, J=7.8 Hz, 3H), 3.77 (s, 3H), 3.83 (d, J=6.3 Hz, 2H), 6.84 (d, J=15.6 Hz, 1H), 6.95-7.00 (m, 3H), 7.50-7.58 (m, 3H), 7.92-8.04 (m, 3H), 8.14 (d, J=15.3 Hz, 1H); ESI-MS (m/z) 470.45 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]2[N:27]([C@H:28]3[CH2:32][CH2:31][NH:30][CH2:29]3)[CH:26]=[N:25][N:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]2[N:27]([C@H:28]3[CH2:32][CH2:31][N:30]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:29]3)[CH:26]=[N:25][N:24]=2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCNC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCN(S(C)(=O)=O)C2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To 4-tert-butyl-N-[4-chloro-2-((S)-4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide hydrochloride (0.25 g, 0.505 mmol) in THF (8 mL) was added pyridine (0.60 mL, 7.4 mmol). The resultant solution was stirred for 20 minutes at room temperature. The reaction mixture was subsequently cooled to 0° C., methanesulfonyl chloride (0.595 mL, 7.6 mmol) was added, and the mixture was stirred overnight at room temperature. The following day, the volatiles were evaporated and the resultant residue was adsorbed onto silica gel and purified by automated normal-phase chromatography (using 50→100% EtOAc in hexanes) to obtain the title compound (0.183 g) in 67.5% yield: MS (ES) M+H expected 538.0, found 538.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]([CH3:9])=[CH2:8]>CCCCC>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: OCCCCl
Reactant: C=C(C)C
Solvent: CCCCC
Product: CC(C)(C)OCCCCl
Yield: 98.06 %

Procedure:
A three-necked, 3-liter Morton flask was equipped with a mechanical stirrer, a Claisen adapter, a thermocouple, a dry-ice condenser with a gas inlet, and a dip tube. The glassware was dried in an oven at 125° C. overnight, assembled hot, and purged under argon until cool. The reaction flask was then charged with Amberlyst® 15 resin (42.0 grams), 3-chloro-1-propanol (4.65 moles, 1 equivalent, 440.0 grams), and pentane (3.7 equivalents, 2000 mL). These reagents were stirred at 500 RPMs. The alcohol was not completely soluble in the organic solvent. A cylinder of 2-methylpropene was attached to the dip tube and 261.16 grams (4.65 moles, 1 equivalent) was fed into the reaction vessel. The feed rate was approximately 2 grams/min. As the conversion of starting alcohol material into product proceeded, the reaction mixture became one liquid phase. The formation of the product was monitored via Gas Chromatography. After all the starting material was consumed, the solution was then pumped into a pressure filter where the Amberlyst® resin catalyst was separated from the product. The resin was washed with fresh pentane (2×100 ml.). The product was purified by distillation from 20 grams of potassium carbonate through a twelve inch Vigreaux column, under reduced pressure. This afforded a clear, colorless oil, yield=598.82 grams (83.75%). Boiling Point=64° C. at 60 mm Hg. GC assay=0.00% 2-methylpropene, 0.81% pentane, 1.13% 3-chloro-1-propanol, and 98.06% desired product. NMR(CDCl3): 3.63 (t, J=6 Hz, 2H), 3.46 (t, J=6 Hz, 2H), 2.28-1.62 (m, 2H), and 1.21 (s, 9H) ppm.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH3:18][NH2:19]>C(O)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:19][CH3:18])#[N:2]
Reactant: CN
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Solvent: CCO
Product: CNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 22 h

Procedure:
A solution of 12.3 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 20 ml of 33% ethanolic methylamine in 200 ml of ethanol was heated at reflux with stirring for 22 hours. The solvent was then removed by evaporation in vacuo, leaving the crude product as a glassy, amorphous solid. Crystallization from a mixture of isopropyl acetate, methylcyclohexane and 2-propanol gave 7.03 g of N"-cyano-N-methyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 169°-170° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C([Li])CCC.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.Cl>O1CCCC1.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1
Reactant: CC1=NCCS1
Reactant: BrCCCCCCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: BrCCCCCCCCC1=NCCS1
Temperature: -70 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 2-methyl-2-thiazoline (1.01 g) in dry tetrahydrofuran at −70° C. was added a solution of n-butyl lithium in hexanes (2.5M, 4.0 ml) dropwise over 10 min. After stirring at −70° C. for 2 h, 1,7-dibromoheptane (12.9 g) was added in one portion (temperature increased to −45° C.). The mixture was cooled again to −70° C. for 1 h and then allowed to warm to room temperature over 1 h. The mixture was cooled to 0° C. and water (10 ml) added, followed by dilute hydrochloric acid (to pH 2). The organic layer was separated and the aqueous layer extracted with diethyl ethyl (2×20 ml). The organic layers were combined and washed with water and brine and dried over magnesium sulfate. Evaporation under reduced pressure gave an oil that was chromatographed on silica gel using 40-60° C. petroleum ether:ethyl acetate 5:1 to give 1-bromo-8-(2-thiazolinyl)octane (1.06 g). 1H-NMR (CDCl3) δ 1.2-1.5 (6H, m), 1.5-1.75 (4H, m), 1.75-1.95 (2H, m), 2.50 (2H, t), 3.28 (2H, t), 3.40 (2H, t) and 4.21 (2H, dt).
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([OH:16])=O.P(Cl)(Cl)(Cl)=O.[C:27]([O:36]C)(=[O:35])[C:28]1[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH2:30]>N1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([NH:30][C:29]1[C:28](=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([OH:36])=[O:35])=[O:16]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: COC(=O)c1ccccc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 63.6 %

Procedure:
To a mixture of 20 ml of dry dioxane and 0.7 g of dry pyridine were added 2 g of 3,4-dimethoxycinnamic acid, 1.6 g of phosphorus oxychloride and 1.6 g of methyl anthranilate. The mixture was heated under reflux for 2 hours to effect reaction. After completion of the reaction, the reaction mixture was concentrated and the residue was dissolved with heating in ethanol and then cooled whereby crystals were precipitated. The crystals were separated by filtration and treated in a manner similar to that described in Example 5 to effect hydrolysis of the ester group. The product was recrystallized from chloroform to obtain 2 g of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid having a melting point of 211°-213° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:28][CH:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(-c2cncnc2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
5-Bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 118.1, 60 mg, 0.130 mmol), pyrimidin-5-ylboronic acid (24.2 mg, 0.196 mmol), Pd2(dba)3 (2.388 mg, 2.61 μmol), 2-dichlohexylphosphino-2′-4′-6′-triisoprophylbiphenyl (XPhos, 4.97 mg, 10.43 μmol) and K3PO4 (83 mg, 0.391 mmol) were added to a MW vial. The vial was sealed, evacuated/purged with argon, and BuOH was added. The RM was stirred at 100° C. for 16 h. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 45.3 mg, 0.065 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 25% for 0.2 min then 25% to 55% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.31 min, m/z=460.1-461.1 [M+H]+, m/z=458.2-459.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.39 (m, 2H) 1.56-1.65 (m, 1H) 1.77-1.86 (m, 1H) 2.63 (dd, J=11.86, 8.44 Hz, 1H) 2.75-2.84 (m, 1H) 3.25-3.38 (m, 1H) 3.43-3.55 (m, 2H) 4.74 (d, J=3.91 Hz, 1H) 7.37 (d, J=8.80 Hz, 2H) 7.86 (d, J=9.05 Hz, 2H) 8.19 (d, J=2.20 Hz, 1H) 8.80 (d, J=2.20 Hz, 1H) 9.08 (s, 2H) 9.21 (s, 1H) 10.30 (s, 1H).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1>C1COCC1>[Cl:13][C:6]1[N:5]=[C:4]([NH:2][CH3:1])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Methylamine 2M in THF (67 mL, 134 mmol) was added to a stirred solution of 2,6-dichloro-3-nitropyridine (12, 93 g, 67 mmol) in THF (100 mL) at 0° C. and the resulting mixture was stirred at RT for 16 hr. The reaction was concentrated under reduced pressure; the residue was partitioned between water and EtOAc and both phases separated. The aq. layer was extracted with EtOAc, the combined organic layer were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (25% EtOAc/hexane) to afford the title product (10.54 g, 53.4 mmol, 80% yield) as yellow solid. tR: 0.96 min (LC-MS 2); ESI-MS: 187 [M+H]+ (LC-MS 2); Rf=0.72 (25% EtOAc/hexane).