Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C>C(OCC)C.Cl.O1CCOCC1>[Cl-:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][NH3+:15]
Reactant: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: [Cl-]
Product: [NH3+]CCNc1ccc2ccccc2c1Cl
Temperature: 0 °C
Reaction time: 7 h
Yield: 92 %

Procedure:
To a cooled (0° C.) single necked flask containing a solution of tert-butyl {2-[(1-chloronaphthalen-2-yl)amino]ethyl}carbamate in 4 mL of ethyl ether, 5 mL of 4 M HCl solution in dioxane were added. The resulting mixture was stirred at room temperature for 7 h. The reaction mixture was concentrated under reduce pressure to afford 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride as a pink solid (92% yield) which was pure by TLC and NMR analysis.
Reaction SMILES: Br[CH2:2][C@H:3]([CH3:23])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].FC1C=CC=C[C:26]=1[N:31]1C2C=CC=CC=2NS1(=O)=O.BrC[C@H](C)CO>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][C@@H:3]([CH3:23])[CH2:2][NH:31][CH3:26])[S:6]1(=[O:22])=[O:21]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Reactant: C[C@@H](CBr)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: C[C@H](CO)CBr
Product: CNC[C@H](C)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to Example 19, step 1, 1-[(2R)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and (R)-3-bromo-2-methylpropan-1-ol giving 0.27 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=1)[C:5](Cl)=[O:6].CN(C=O)C.[NH2:20][C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[OH:31].C(N(CC)CC)C>O>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([OH:31])=[C:21]([NH:20][C:5](=[O:6])[C:4]2[C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=2)[CH:26]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: O=C(Cl)c1cc(Cl)ncc1C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(O)c(NC(=O)c2cc(Cl)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.66 g of 2-chloro-5-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give 2-chloro-5-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 2-chloro-5-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.48 g of 2-amino-4-tert-butylphenol, 0.59 g of triethylamine and 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and stirred while heating at 50° C. for one hour. The mixture was cooled to room temperature, and water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.75 g of N-(5-tert-butyl-2-hydroxyphenyl)-2-chloro-5-trifluoromethylisonicotinamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:32]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.FC1C=CC=C(F)C=1NC(N1CCC(OC2C=CC(NC3C4C=C(F)N=CC=4N=CN=3)=CC=2C)CC1)=O>>[CH:32]1([NH:37][C:38]([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:15][C:16]4[C:17]5[CH:25]=[C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)[N:23]=[CH:22][C:18]=5[N:19]=[CH:20][N:21]=4)=[CH:3][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1
Reactant: O=C=NC1CCCC1
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)Nc2c(F)cccc2F)CC1
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCN(C(=O)NC2CCCC2)CC1

Procedure:
The title compound was prepared from [3-Methyl-4-(piperidin-4-yloxy)-phenyl]-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine and cyclopentyl isocyanate by a procedure analogous to the synthesis of 4-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidine-1-carboxylic acid (2,6-difluoro-phenyl)-amide above. LRMS: 532.3/421.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.57 (s, 1H), δ 8.78 (s, 1H), δ 8.32 (s, 1H), δ 7.48-7.54 (m, 3H), δ 7.12 (d, J=9.14 1H), δ 6.24 (d, J=7.30, 1H), δ 4.50-5.19 (m, 1H), δ 3.84-3.89 (m, 1H), δ 3.74-3.76 (m, 4H), δ 3.51-3.59 (m, 6H), δ 3.12-3.18 (m, 2H), δ 2.16 (s, 3H), δ 1.81-1.86 (m, 4H), δ 1.29-1.76 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2F)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 27.7 %

Procedure:
To a solution of ethyl 2-[(2-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0 mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient temperature. The mixture was refluxed for 36 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.037 g, y. 27%).
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([N:46]=[C:47]=[S:48])=[O:45]>C1(C)C=CC=CC=1.C(O)C>[F:49][C:37]([F:36])([F:50])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([N:46]=[C:47]=[S:48])=[O:45].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:47]([NH:46][C:44](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[C:37]([F:36])([F:50])[F:49])=[S:48])=[CH:31][CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 95%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])(C)(C)C.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20].[NH2:24][C:25]1[C:33]([Cl:34])=[CH:32][C:28](C(O)=O)=[C:27]([O:35][CH3:36])[CH:26]=1>>[NH2:24][C:25]1[C:33]([Cl:34])=[CH:32][C:28]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:22]([NH:21][CH2:18][CH2:19][CH3:20])=[O:23])[CH2:11]2)=[O:7])=[C:27]([O:35][CH3:36])[CH:26]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: CCCN=C=O
Product: CCCNC(=O)NCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-propyl isocyanate (0.38 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.83 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(2-(3-n-propylureido)ethyl)pyrrolidin-3-ylmethyl)-benzamide.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)([O-:3])=[O:2].[CH2:19]([NH2:21])[CH3:20]>>[N+:1]([CH:4]=[C:5]([NH:21][CH2:19][CH3:20])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1
Product: CCNC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene (see Example 85 (I)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(-c2ncco2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ncco3)cc2)CC1

Procedure:
Prepared in analogy to example 4.4(a) from 2-(4-Bromo-phenyl)-oxazole and N-BOC-piperazine. MS (m/e): 330.3 (MH+, 100%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 68 °C
Yield: 55.3 %

Procedure:
Titanium (IV) chloride (0.36 g, 1.89 mmol) was added drop wise to a suspension of zinc powder (0.25 g, 3.78 mmol) in THF (3 ml). This solution was heated at 68° C. for one hour, then cooled to RT before (3SR,4RS)-1-benzyl-3-(4-chloro-phenyl)-4-nitro-pyrrolidine (0.20 g, 0.63 mmol) in THF (2 ml) was added. The reaction mixture was then stirred at reflux over night. The reaction was cooled to RT, diluted with 300 ml of Et2O, washed with an aqueous solution of NaHCO3 and the organic phases were dried over Na2SO4. Flash chromatography (SiO2, CH2Cl2/MeOH, 9:1) yielded 0.10 g (57%) of (3RS,4SR)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine as a light yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:10]1([C:16]([NH:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of trans-4-aminocyclohexanol hydrochloride (2.00 g; 13.19 mmol), triphenylmethyl chloride (4.41 g; 15.83 mmol) and triethylamine (6.44 ml; 46.17 mmol) in 40 ml CH2Cl2 is refluxed overnight. The solids are filtered off and the residue concentrated in vacuo. The resultant product is purified with CH2Cl2 CH2Cl2: ethylacetate (5:1) to obtain trans-4-triphenylmethylaminocyclo-hexanol which is used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[N:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25](O)=[O:26])[CH:23]=4)=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[CH:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]([N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:26])[CH:23]=4)=[CH:17][N:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: C1CCNCC1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CC(=O)O)c4)cn3)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CC(=O)N5CCCCC5)c4)cn3)c2)cn1
Temperature: 50 °C
Yield: 15.1 %

Procedure:
A mixture of (4-{2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-5-yl}-1H-pyrazol-1-yl)acetic acid (example 9, 110 mg; 0.31 mmol; 1.0 eq.), piperidine (52 mg; 0.61 mmol; 2.0 eq.), HATU (174 mg; 0.46 mmol; 1.50 eq.) and DIEA (152 μl; 0.92 mmol; 3.0 eq.) in DMF (2 mL) was stirred at 50° C. O/N. The reaction mixture was poured into water and extracted with DCM (three times). Combined organic phases were then concentrated under reduced pressure and the residue was recrystallised in MeOH/Ether. The solid obtained was filtered and dried under reduced pressure to give the title compound as a white solid (20 mg, 15%). 1H NMR (300 MHz, DMSO) δ 9.18 (s, 2H), 8.54 (t, J=1.6 Hz, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.25-8.19 (m, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.77-7.66 (m, 1H), 7.52 (t, J=7.8 Hz, 1H), 5.22 (s, 2H), 3.90 (s, 3H), 3.55-3.39 (m, 4H), 1.69-1.39 (m, 6H).HPLC (Condition A): Rt 3.16 min (purity 99.9%). MS (ESI+): 428.3
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2.[CH:16]([NH2:19])([CH3:18])[CH3:17]>O1CCOCC1>[CH:16]([NH:19][CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2)([CH3:18])[CH3:17]
Reactant: c1cc2c(c(OCC3CO3)c1)SCCC2
Reactant: CC(C)N
Solvent: C1COCCO1
Product: CC(C)NCC(O)COc1cccc2c1SCCC2

Procedure:
A mixture of 6.9 g of crude 8-(2,3-epoxy propyloxy) thiochroman prepared as described above, 26 ml of isopropylamine and 53 ml of dry dioxan were refluxed for 20 hours. The reaction mixture was then evaporated to dryness, under vacuum. The residue was taken up with chloroform and diluted hydrochloric acid. The acid aqueous phase was made alkaline with an aqueous sodium hydroxide solution. There were obtained 4.6 g of dl 8-(3-isopropylamino-2-hydroxy propyloxy) thiochroman, melting (K) at 90° to 92°C, which recrystallized in cyclohexane, melted at 91 to 92°C. 3.9 g of this base were dissolved in 20 ml of ethanol and a solution of dry hydrochloric gas in ether was added.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:24][S:25](O)(=[O:27])=[O:26].P(Cl)(Cl)(Cl)=O>ClCCl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:19][C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:17])=[CH:12][C:11]=1[S:25]([Cl:24])(=[O:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCOc1ccc(C(C)(C)CC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(C(C)(C)CC(C)(C)C)cc1S(=O)(=O)Cl

Procedure:
In 900 ml of dichloromethane was dissolved 159 g of Compound A and the solution was stirred while cooling with an ice bath. After slowly adding dropwise 41.5 ml of chlorosulfonic acid to the solution, the mixture was stirred for 1.5 hours. Then, dichloromethane was removed while reducing the pressure by a tap aspirator and 480 ml of N,N-dimethylacetamide and 150 ml of acetonitrile were added to the residue formed. After adding dropwise 93.2 ml of phosphorous oxychloride to the mixture over a period of 40 minutes, the resultant mixture was stirred for 1.5 hours at 40° C. The solution was extracted four times with 500 ml of hexane and the hexane layer was collected and concentrated to provide 229 g of a crude product of 2-octyloxy-5-t-octylbenzenesulfonyl chloride (Compound B). The crude product was used as it was in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][C@H:13]([CH3:17])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][C@H:11]([CH3:10])[N:12]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@H:13]([CH3:17])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.8 %

Procedure:
A mixture of 4-bromobenzaldehyde (1.85 g, 10 mmol), 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-1-piperazinecarboxylate (2.15 g, 10 mmol) and sodium triacetoxyborohydride (3.18 g) in 1,2-DCE (35 ml) was stirred at room temperature for 3 days. Saturated aq. NaHCO3 solution was added and the mixture stirred for 30 mins. The product was extracted into EtOAc and the extracts dried (Na2SO4) and concentrated. The residue was dissolved in DCM and treated with PS-hydrazine resin with stirring for 2 h. The resin was removed by filtration and the solvent removed in vacuo. Chromatography (0-40% EtOAc/hexane) gave the title compound (3.52 g). MS (ES): MH+ 383/385.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[C:25]1([NH:31][C:32]([C:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([C:32]([NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:33])[CH:35]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1ccccc1)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3cccc(C(=O)Nc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 96 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 330 and using tert-butyl 4-{4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate and (3-phenylaminocarbonylphenyl)boronic acid as starting material, 334 mg (96%) of the desired product was isolated. LC-MS m/z [M+H]+ 513.2, RT 3.13 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(F)cc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Chloro-4-fluoro-benzoic acid. LC-MS (basic): tR=0.91 min; [M+H]+=484.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[N:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([O:39]C)=[O:38])#[N:2].O.[OH-].[Li+].O.Cl.O1CCOCC1>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[N:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([OH:39])=[O:38])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)n4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)n2)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
A mixture of methyl 6-cyano-7-(4-(6-(3,4-dimethylphenyl)pyridin-2-ylcarbamoyl)phenoxy)-chroman-4-carboxylate (51.1 mg, 0.09577 mmol), 1.0 M lithium hydroxide monohydrate solution in water (191.5 μl, 0.1915 mmol), and THF (1.5 ml) was stirred for 3 days at ambient temperature. The mixture was quenched with 4.0 M HCl solution in 1,4-dioxane (71.83 μl, 0.2873 mmol). The mixture was purified on silica gel (MeOH in dichloromethane gradient with 1% acetic acid) to provide 42.8 mg of the title compound was obtained as a thin film (86%). MS (apci) m/z=520.2 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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.O.CCOCC>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:3]([N:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]4)=[C:4]3[CH:10]=[N:9]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Temperature: 80 °C
Yield: 88.9 %

Procedure:
tert-Butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.50 g, 0.995 mmol), phenylboronic acid (0.182 g, 1.49 mmol), Pd(PPh3)4 (0.115 g, 0.0995 mmol) and Cs2CO3 (1.30 g, 3.98 mmol) were placed in dioxane:H2O (8 mL, 3:1). The solution was heated to 80° C. for 6 hours. Ether (50 mL) and H2O (20 mL) were then added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (DCM:ethyl acetate=5:1) to give tert-butyl 4-(1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.442 g, 89%) as a foam solid. MS ESI (+) m/z 500.4 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.26 (s, 1H), 8.10 (s, 1H), 7.51 (m, 2H), 7.44 (m, 2H), 7.32 (m, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 5.50 (s, 2H), 3.67 (s, 3H), 3.23 (m, 4H), 3.20 (m, 4H).