Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[NH2:31]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1c(F)cccc1F
Product: Cc1nc(NCc2ccccn2)nc(Nc2c(F)cccc2F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,6-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (s, 3H), 2.33 (s, 3H), 4.50 (bs, 2H), 5.88 (bs, 2H), 6.80-7.01 (m, 2H), 7.03-7.21 (m, 3H), 7.53 (bs, 1H), 8.47 (bs, 1H); MS (ESI) m/z 342.6 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH3:21][C:22]1([CH3:34])[CH2:26][C:25](=[O:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23]1>C1COCC1>[CH3:21][C:22]1([CH3:34])[CH2:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)([OH:27])[C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23]1
Reactant: CC1(C)C=C(c2ccccc2)C(=O)C1
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C2(O)CC(C)(C)C=C2c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-bromothioanisole (2.51 g, 12.3 mmol) in THF (20 mL) at −78° C. was added dropwise a solution of 2.5 M n-butyl lithium in hexane (4.8 mL, 12.0 mmol). The resulting suspension was stirred at this temperature for 1 h and then a solution of 4,4-dimethyl-2-phenyl-2-cyclopenten-1-one from Step 2 (1.25 g, 6.7 mmol) in THF (20 mL) was added slowly via cannula to the cold reaction. The reaction was stirred for 15 min at −78° C. and then for 30 min. at r.t. The reaction was stopped by dilution with NH4OAc buffer 25% w/v and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 10% EtOAc/hexanes to give the title compound as a colorless gum.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].CCN(C(C)C)C(C)C.[C:22]([N:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31](O)=[O:32])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.N1CCC[C@H]1C(O)=O>C(Cl)Cl>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:31]([C@@H:30]2[CH2:34][CH2:35][CH2:36][N:29]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:32])=[CH:7][CH:8]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a suspension of 2-amino-4′-bromoacetophenone hydrochloride 17 (5.0 g, 20.0 mmol) in DCM (150 mL) was added DIPEA (2.6 g, 20 mmol) at room temperature. After stirred for 10 minutes, the suspension became yellow solution. To another flask charged with a DCM (100 mL) solution of N-Boc-L-Proline (5.2 g, 24.0 mmol) was added HOBt.H2O (3.7 g, 24.0 mmol) at room temperature. EDC.HCl (4.6 g, 24.0 mmol) was added to the proline mixture and the mixture was continually stirred at room temperature for 30 minutes. The above-mentioned yellow solution was added to the proline mixture and stirred at room temperature overnight. The resulting mixture was filtered through Celite® to remove the precipitate. The filtrate was extracted with H2O/DCM, and the organic layer was washed with brine, dried over MgSO4, and filtered. After being concentrated under reduced pressure, the crude product was purified by column chromatography (ethyl acetate: n-hexane=2:5) to yield pure product 18a as a yellow gel (7.4 g).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light grey solid (74 mg, 91%), MS (ISP) m/z=325.4 [(M+H)+], mp 237° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][CH:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][CH:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCC(O)C3)n1)CCN(CC(C)O)CC2
Yield: 61 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as a white solid (70 mg, 61%). mp: 199-202° C., MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.55 (m, 2H), 7.25 (m, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.89 (s, 4H), 3.43 (m, 3H), 2.89-2.52 (m, 9H), 2.26 (t, J=9 Hz, 1H), 1.96 (m, 1H), 1.87 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:36]>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:40]5[CH2:41][CH2:42][N:37]([CH2:35][CH3:36])[CH2:38][CH2:39]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1CCNCC1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: CCN1CCN(Cc2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Yield: 1.2 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 1-ethyl-piperazine as starting materials, 3.4 mg (1.2%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.00 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.50 (s, 2 H), 2.40-2.20 (m, 10), 1.0 (t, 3 H); ES-MS m/z 543.01 [M+H]+, HPLC RT (min) 2.28.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:34])=[C:21]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:45]=[C:44]2[CH:39]([CH2:40][CH2:41][N:42]([C:46](=[O:51])[C:47]([F:50])([F:49])[F:48])[CH2:43]2)[CH2:38][CH:37]=1.Cl>O1CCOCC1.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:21]1[CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:35][C:36]4[CH:45]=[C:44]5[C:39]([CH2:40][CH2:41][N:42]([C:46](=[O:51])[C:47]([F:50])([F:48])[F:49])[CH2:43]5)=[CH:38][CH:37]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=[CH:19][C:20]=1[F:34])=[O:33]
Reactant: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F)c1c(F)cccc1F
Reactant: NC1=CCC2CCN(C(=O)C(F)(F)F)CC2=C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)ccc1F)c1c(F)cccc1F
Temperature: 80 °C
Yield: 46.6 %

Procedure:
To a solution of N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2,6-difluorobenzamide (162 mg, 0.34 mmol) in 1,4-dioxane (6 mL) and 2-propanol (2 mL) was added 7-amino-N-trifluoroacetyl tetrahydroisoquinoline (165 mg, 0.68 mmol) followed by catalytic 12M HCl. After heating overnight at 80° C., reaction was quenched with saturated NaHCO3 (25 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (25 mL), organic layer concentrated, and purified by column chromatography (5-50% EtOAc in hexanes) to provide the product (109 mg, 47%) as an off-white solid. ESIMS (M+H)+=688.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:24]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])[CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:18]([F:27])([F:28])[F:17])=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccc(C(F)(F)F)cc1
Yield: 34.6 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.32 ml (2.22 mmol) para-trifluoromethylbenzylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 480 mg (31%) of the title compound as a light brown oil. MS m/e (%): 626 (M+H+, 100). ps b) (R)-1-[3-[3-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propylamino]-propionyl]-pyrrolidine-2-carboxylic Acid tert-Butyl Ester and (R)-1-[3-[[3-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-ethyl-amino]-propionyl]-pyrrolidine-2-carboxylic Acid tert-Butyl Ester
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10](Br)=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35]>CCCCCC.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:34]=[O:35])=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(C=O)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Yield: 44 %

Procedure:
0.58 g (1.4 mmol) of 1-benzyl-7-benzylamino-3-bromo-2-methylpyrrolo[2,3-d]pyridazine, 3.5 ml (5.7 mmol) of 15% strength solution of n-butyllithium in hexane and 0.55 ml (7 mmol) of dimethylformamide are reacted in 40 ml of anhydrous tetrahydrofuran as described for Example 2a. Yield: 44%, m.p.: 171°-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:25])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2scc(-c3cccc(OC)c3)c2c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(OC)c3)c2c1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.7 %

Procedure:
To a stirred solution of ethyl 4-amino-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-5-carboxylate (865 mg, 2.53 mmol) (Description 14) in DCM (18 mL), was added N-bromosuccinimide (540 mg, 3.03 mmol) and the resulting mixture stirred for 45 min at RT. The mixture was concentrated and purified by chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, to give the title compound (1.02 g). LCMS (A) m/z: 421/423 [M+1]+, Rt 1.57 min (acidic).
Reaction SMILES: C[O:2][C:3](=[O:26])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)/[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 47.5 °C
Reaction time: 15 h
Yield: 100.5 %

Procedure:
A solution of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylic acid methyl ester (1.8 g, 4.6 mmol) in ethanol (20 mL) was treated with a 1N aqueous sodium hydroxide solution (15 mL). The solution was heated at 45-50° C. For 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (40 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (1.74 g, 99%) as a white solid: mp 62-64° C.; EI-HRMS m/e calcd for C17H19F3O4S (M+H)+377.1034, found 377.1041.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.C(OC([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.[ClH:47].CN(C)CCCN=C=NCC>C(Cl)Cl.O>[ClH:47].[ClH:47].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:26]([C@@H:25]([NH2:24])[CH3:29])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[C:3]=1[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-3-methyl-N2-phenylbenzene-1,2-diamine (600 mg, 2.77 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (577 mg, 3.05 mmol), HOAt (415 mg, 3.05 mmol), 4-methylmorpholine (0.67 mL, 6.1 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (586 mg, 3.05 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1.[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[N:12]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(CCCO)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(CCCO)n2)sc2ccccc12
Yield: 15 %

Procedure:
6-(3-Hydroxypropyl)-2-pyridinecarbonitrile (2.2 g, 13.6 mmol) and methyl thiosalicylate (3.7 g, 22.0 mmol) were dissolved in toluene (15 ml), and triethylamine (3.0 ml, 21.7 mmol) was added thereto. The reaction mixture was refluxed for 30 hrs and subjected to a silica gel (170 g) column chromatography. The fractions eluted with ethyl acetate were collected and concentrated to give the titled compound (0.61 g, 15%) as white crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[I:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[CH3:17]>ClC1C=CC=CC=1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>[I:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[CH2:17][Br:1]
Reactant: Cc1ccc(Br)cc1I
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: Clc1ccccc1
Product: BrCc1ccc(Br)cc1I
Yield: 24.2 %

Procedure:
N-Bromosuccinimide (NBS) (1.1 molar equivalents, 66.5 g, 373 mmol) and benzyl peroxide (0.006 molar equivalent, 450.7 mg, 1.9 mmol) are added to a solution of 2-iodo-4-bromotoluene 6 (1 molar equivalent, 100.3 g, 338 mmol) in chlorobenzene (1200 ml). The batch is then stirred under reflux overnight. After the solvent has been removed in a rotary evaporator, ethyl acetate and water are added. The aqueous phase is extracted by shaking with ethyl acetate. The organic phase is washed by shaking with water, dried and evaporated in a rotary evaporator. The product 7 (30.7 g, 24%) is obtained in the form of a white powder by recrystallisation from ethanol (50 ml).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([C:15]([O-:17])=[O:16])=[CH:7]2)[CH2:3][CH2:2]1.[C@H:18]12[CH2:24][C@H:21]([CH2:22][CH2:23]1)[CH2:20][C:19]2=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2)[CH2:3][CH2:2]1
Reactant: O=C([O-])C1=CC2(CCNCC2)c2ccccc21
Reactant: O=C1C[C@H]2CC[C@@H]1C2
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: CC(Cl)Cl
Product: O=C(O)C1=CC2(CCN(C3CC4CCC3C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound (D1) (0.020 g, 0.058 mmol), titanium (IV) isopropoxide (0.052 mL, 0.174 mmol), and (1R,4S)-bicyclo[2.2.1]heptan-2-one (3 eq) was stirred at room temperature for 18 h in dichloroethane (0.5 mL). Sodium triacetoxyborohydride (0.012 g, 0.058 mmol) was added and stirred at room temperature for 1 h. The solvent was evaporated and 6N NaOH (0.5 mL) and methanol (1 mL) was added and then triturated to form a white solid. The solid was washed with methanol (1 mL) and EtOAc (1 mL). The filtrate was concentrated under reduced pressure to afford the crude product which was purified by reverse phase preparative HPLC to afford 1′-(bicyclo[2.2.1]heptan-2-yl)spiro[indene-1,4′-piperidine]-3-carboxylic acid (Compound No. 48) (0.002 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 324.1 (M+1), Rt 1.9 minutes.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].CN(C)C=O.O>ClCCl>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]1[C:15](=[O:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18]1=[O:20]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCCCCCCCCBr
Agent: [K]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Temperature: 160 °C

Procedure:
1,12-dibromododecane (32.22 g, 98.2 mmol), potassium phthalimide (4.60 g, 24.5 mmol), and dimethylformamide (20 mL) were combined and refluxed at 160° C. for 2.5 hours. Upon cooling, water was added and the organic taken into dichloromethane (separated on a separatory funnel). The solvent was evaporated under reduced pressure and the crude product was columned in hexanes. The spots were not separated, and the fractions were combined, the solvent removed, and the crude material re-dissolved in 300 mL acetone. This was refluxed, and 10 g potassium phthalimide was added over 4 hours. The mixture was refluxed overnight. After cooling and removing the solvent, the crude product was columned using 1:1 ethyl acetate: hexanes. The top spot proved to be the desired product, which was collected as a white solid (9.30 g) that matched the reported literature: Helv. Chimica Acta. 2001, 84(3), 678-689.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1>CO>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[CH:12][CH:11]=1
Reactant: Cn1cncc1-c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: Cn1cncc1-c1ccc(N)cc1

Procedure:
Prepared by hydrogenation of 1-methyl-5-(4-nitro-phenyl)-imidazole in MeOH on palladium/charcoal (10%) at 20° C. and 3.5 bar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[C:13]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[N:12]=[C:11]2[O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccc(OC)cc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [7-Methoxy-1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).