Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[F:17][C:18]([F:26])([F:25])[C:19]([C:20]1[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:21]=1[CH3:22])=[O:24]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2cccs2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
To a stirred solution of 59 mg (0.24 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-2-yl-methanone in 2 ml acetic acid was added 0.038 ml (0.24 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 20:1) afforded 19 mg (22%) 2,2,2-trifluoro-1-(2-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-ethanone as a colorless oil. ES-MS m/e (%): 368 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[CH:23][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[O:32][C:33]=3[CH3:34])=[CH:23][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A mixture of ethyl [1-benzyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (731 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-benzyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetic acid (580 mg, yield 84%), which was then recrystallized from acetone-hexane. melting point: 91–92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[C:6]([F:9])[C:7]=1I.FC1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=CC=1[C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[C:6]([F:9])[C:7]=1[C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Reactant: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cn1
Product: COc1ccc(-c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cn1

Procedure:
N-({(5S)-3-[3,5-difluoro-4-(6-methoxypyridin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide is prepared by the route described in Example 1 substituting N-{[(5S)-3-(3,5-difluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide for N-({(5S)-3-[3-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide. 1H-NMR (DMSO) δ: 8.25, 7.61, 7.30, 4.73, 4.10, 3.72, 3.49, 3.40, 2.30, 1.90, 1.83
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:14]1[N:19]=[C:18]2[NH:20][C:21](=[O:33])[N:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[C:23](=[NH:24])[C:17]2=[CH:16][N:15]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[N:22]1[C:23](=[NH:24])[C:17]2[C:18](=[N:19][C:14]([NH:12][C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]4)=[CH:8][CH:7]=3)=[N:15][CH:16]=2)[NH:20][C:21]1=[O:33]
Reactant: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(F)cccc1Cl
Reactant: CN1CCc2ccc(N)cc2C1
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: CN1CCc2ccc(Nc3ncc4c(=N)n(-c5c(F)cccc5Cl)c(=O)[nH]c4n3)cc2C1

Procedure:
32 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2-chloro-6-fluorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 3 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:13])=[CH:7][C:8]=2[CH3:12])[CH2:3]1.Cl[C:15]1[N:20]=[C:19]2[NH:21][C:22](=[O:34])[N:23]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[C:24](=[NH:25])[C:18]2=[CH:17][N:16]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH3:32])[C:26]=1[N:23]1[C:24](=[NH:25])[C:18]2[C:19](=[N:20][C:15]([NH:13][C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]4)=[C:8]([CH3:12])[CH:7]=3)=[N:16][CH:17]=2)[NH:21][C:22]1=[O:34]
Reactant: Cc1cc(N)cc2c1CCN(C)C2
Reactant: Cc1cccc(Cl)c1-n1c(=O)[nH]c2nc(Cl)ncc2c1=N
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: Cc1cc(Nc2ncc3c(=N)n(-c4c(C)cccc4Cl)c(=O)[nH]c3n2)cc2c1CCN(C)C2

Procedure:
7 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2-chloro-6-methylphenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 2 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[C:68]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][CH2:79][OH:80])[CH2:74][CH2:73]5)[CH:69]=[CH:70][CH:71]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[C:53]([CH3:91])=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[C:68]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][CH2:79][OH:80])[CH2:74][CH2:73]5)[CH:69]=[CH:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[C:53]([CH3:91])=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(N5CCN(CCO)CC5)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(N4CCN(CCO)CC4)c3)cc12
Yield: 15.7 %

Procedure:
Using the same reaction conditions as described in step-iii of example-1, 2-(4-(3-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) piperazin-1-yl)ethanol (58 mg, 0.085 mmol) was hydrolyzed by lithium hydroxide (36 mg, 0.85 mmol), THF/Methanol/water (12/6/3 ml) to yield 7 mg (16%) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.46-8.45 (d, 1H), 7.87-7.86 (d, 1H), 7.39-7.31 (m, 3H), 7.16 (s, 1H), 7.10-7.08 (m, 1H), 7.04-6.97 (m, 3H), 6.87-6.84 (m, 1H), 3.75-3.74 (t, 2H), 2.82 (b, 4H), 2.53 (m, 2H), 2.21 (s, 3H), 2.17 (s, 3H). MS: m/z=525.0 (M+1), HPLC: 91.007% in method A.
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:15][N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: Clc1ccc(Br)cc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Clc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 64 %

Procedure:
Benzophenone hydrazone (1 equiv., 10 mmol, 2.04 g), 4-chlorobromobenzene (1.0 equiv., 10 mmol, 1.915 g), Pd(OAc)2 (0.01 equiv., 0.1 mmol, 23 mg), BINAP (0.01 equiv., 0.1 mmol, 63 mg), and toluene (5 mL) were added to an oven dried Schlenk flask and stirred at room temperature for 2 minutes, NaOtBu (1.4 equiv., 14 mmol, 1.345 g) and an additional 5 mL of toluene were then added. The flask was capped with a septum and purged briefly with argon (˜1 min.) and heated to 80° C. under argon for 13 hours. The reaction mixture was then cooled to room temperature, diluted with Et2O (10 mL), and concentrated under vacuum to give the crude product as a brown solid. Recrystallization of the crude product from hot isopropanol (100 mL) gave the desired product as a yellow solid (1.971 g, 6.4 mmol, 64% yield). The mother liquor was concentrated under vacuum and purified by column chromatography (5% EtOAc/Hex) to give an additional 550 mg of the desired product (1.79 mmol, 18% yield), to give an 82% overall yield of the title product.
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9]([CH2:16][C:17]([O:19]CC)=[O:18])([CH3:15])[CH2:8][CH2:7]2>O>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9]([CH2:16][C:17]([OH:19])=[O:18])([CH3:15])[CH2:8][CH2:7]2
Reactant: CCOC(=O)CC1(C)CCc2cc(OC)ccc2C1=O
Agent: Br
Solvent: O
Product: CC1(CC(=O)O)CCc2cc(O)ccc2C1=O
Yield: 86.2 %

Procedure:
Aqueous HBr (300 mL) was added to 3A (30 g, 109 mmol), and the reaction mixture was refluxed for 5 h. The reaction mixture was then brought to room temperature, diluted with water and extracted with ethyl acetate (2×300 mL). The separated organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 40% ethyl acetate in hexanes to afford the title compound (22 g, 73%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 12.08 (bs, 1H), 10.29 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 6.7 (m, 1H), 6.62 (m, 1H), 3.0-2.71 (m, 3H), 2.49-2.33 (m, 2H), 1.8 (m, 1H), 1.1 (s, 3H). ESI-MS m/z: 235 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[CH:11].[C:12]([O:16][C:17](=[O:21])[CH:18]=[N+:19]=[N-:20])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([C:18]1[NH:19][N:20]=[C:10]([CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1)=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Reactant: C#CCOCCOCCOC
Product: COCCOCCOCc1cc(C(=O)OC(C)(C)C)[nH]n1
Temperature: 70 °C

Procedure:
To a solution containing approx. 2.5 g 3-[2-(2-Methoxy-ethoxy)-ethoxy]-propyne, 2.8 g Diazo-acetic acid tert-butyl ester were added and the mixture was heated to 70° C. for 5 days. Then the solution was concentrated under reduced pressure and directly purified by chromatography on silica eluting with a n-heptane/ethyl acetate gradient. Yield: 1.7 g.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(#N)C>[C:11]1([CH2:10][O:9][C:8]([NH:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][N:1]2[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NC[C@@H]1CCCN1)OCc1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)N1CCC[C@H]1CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of phenylmethyl [(2S)-2-pyrrolidinylmethyl]carbamate (D114, 1.36 g, 5.81 mmol) and K2CO3 (1.6 g, 11.62 mmol) in acetonitrile (20 ml), cooled to 0° C., was added dropwise diethyl bromomalonate (1.37 ml, 6.97 mmol) in a 2-3 mins time. Then the reaction mixture was allowed to warm-up to room temperature and it was stirred for 4 hrs.
Reaction SMILES: S(O[C@@H:6]1[C@H:10]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:9][C@H:8]([N:20]2[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:7]1)(C)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Li+].CO>CN(C)C=O>[N:29]([C@H:6]1[C@H:10]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:9][C@H:8]([N:20]2[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:7]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H](n2cc(F)c(N)nc2=O)C[C@@H]1OS(C)(=O)=O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H](n2cc(F)c(N)nc2=O)C[C@H]1N=[N+]=[N-]
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
To a solution of 9 (520 mg, 1.19 mmol) in anhydrous dimethylformamide (12 mL) was added lithium azide moistened with 10% methanol (300 mg, 5.31 mmol). The reaction mixture was stirred at 100° C. during 2.5 h, and then cooled to room temperature, poured onto ice/water (200 mL) and extracted with chloroform (3×100 mL). Combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 mL), with water (5×100 mL), and then dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent : methanol (4%) in chloroform] to give pure 10 (327 mg, 72%), which was crystallized from a diethyl ether/methanol mixture: mp 146-147° C.; UV (ethanol): λmax 243 nm (ε 8700), 283 nm (ε8400), λmin 226 nm (ε 7200), 264 nm (ε 6700); 1H NMR (DMSO-d6): δ 7.90 (d, 1H, H-6, J6-F5=7.0 Hz), 7.8-7.5 (br d, 2H, NH2), 6.0 (m, 1H, H-1′), 4.3 (m, 1H, H-3′), 3.9-3.7 (m, 3H, H-4′, H-5′ and H″-5), 2.4-2.2 (m, 2H, H-2′ and H-2″), 0.87 (s, 9H, (CH3)3C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 769 (2M+H)+, 385 (M+H)+, 130 (BH2)+; FAB<0 m/z 383 (M−H)−; [α]D20=−67 (c, 0.96 DMSO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].[CH2:21](O)[CH2:22][CH2:23][CH2:24][OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])(=[O:10])=[O:11]
Reactant: OCCCCO
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCCO)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
A solution of 3-(2-methoxyphenylsulfonyloxy)-5-methylphenol (177 mg, 0.60 mmol, as prepared in step b of example 8), 1,4-butanediol (0.53 mL, 6.0 mmol), triphenylphosphine (316 mg, 1.2 mmol), and anhydrous tetrahydrofuran (4 mL) was cooled to 0° C., then diethyl azodicarboxylate (0.20 mL, 1.2 mmol) was added dropwise over 5 minutes. The solution was stirred at 0° C. for 15 min and then at ambient temperature overnight. Additional triphenylphosphine (3×320 mg) and diethyl azodicarboxylate (3×0.20 mL) were added over the next 3 days. The mixture was filtered, and the filtrate was concentrated. The residue was triturated with 40% ethyl acetate in hexane, then the mixture was filtered and the filtrate was concentrated. Crude product was purified by flash column chromatography through silica gel (40% to 70% ethyl acetate in hexane, then 0% to 2% acetone in dichloromethane in a separate chromatographic separation) to give the title compound as a colorless oil (85.4 mg, 39%). 1H-NMR (300 MHz, CDCl3) δ 7.83 (dd, 1H, J=1.8, 7.9 Hz), 7.61 (ddd, 1H, J=1.7, 7.4, 8.4 Hz), 7.08 (d, 1H, J=8 Hz), 6.99-7.04 (m, 1H), 6.57 (br s, 1H), 6.50 (br s, 1H), 6.44 (t, 1H, J=2.2 Hz), 4.02 (s, 3H), 3.88 (t, 2H, J=6.0 Hz), 3.70 (q, 2H, J=6 Hz), 2.24 (s, 3H), 1.65-1.87 (m, 4H), 1.45 (t, 1H, J=6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Br:13])[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].C[Si](C)(C)[O:17][CH:18](O[Si](C)(C)C)[CH3:19].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(Cl)Cl>[CH2:18]1[O:17][C:9]2([C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:12]([Br:13])[CH:11]=3)[CH2:7][CH2:8]2)[O:14][CH2:19]1
Reactant: CC(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: O=C1CCc2cc([N+](=O)[O-])c(Br)cc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c(cc1Br)C1(CC2)OCCO1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension of 5-nitro-6-bromo-1-indanone (11.0 g, 43 mmol) and bis(trimethylsilyloxy)ethane (22.0 mL, 90 mmol) in CH2Cl2 (90 mL) at room temperature was added trimethylsilyltrifluoromethanesulfonate (100 μL). The mixture was stirred for 2 h and the homogeneous solution was quenched with saturated aqueous NaHCO3 (100 mL). The CH2Cl2 layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel, eluting with ethyl acetate:hexanes (2:5), furnished 10.2 g (79%) of the title compound as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.N1C=CC=C(CN)C=1.[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:9][CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[CH:2][CH:3]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]
Reactant: NCc1cncc(F)c1
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)NCc1cccnc1
Yield: 40 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-3-ylmethanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 40% yield: 1H NMR (300 MHz, CDCl3) δ 8.58-8.52 (m, 2H), 7.69-7.66 (m, 1H), 7.28-7.23 (m, 1H), 6.20-6.17 (m, 1H), 4.57 (d, J=5.8 Hz, 2H), 4.12-4.07 (m, 2H), 3.61-3.55 (m, 2H), 3.10 (d, J=7.4 Hz, 2H), 2.61 (s, 3H), 1.96-1.87 (m, 1H), 0.92 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.4, 155.6, 153.5, 149.1, 148.7, 135.5, 133.9, 123.5, 116.6, 51.5, 42.8, 41.9, 41.2, 26.7, 19.9, 17.2; MS (ES+) m/z 373.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](OC1C=CC=CC=1)=[N:8][CH:7]=[CH:6]2.C([O-])(=O)C.[NH4+:24]>[OH-].[Na+]>[NH2:24][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2c(Oc3ccccc3)nccc2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(N)nccc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of 6-methoxy-1-phenoxyisoquinoline (21.3 g, 85 mmol) and ammonium acetate (55 g) was heated, under a nitrogen atmosphere, to 150° C. and stirred overnight. The mixture was allowed to cool to ambient temperature, after which 3 N sodium hydroxide (280 ml) was added with stirring. The thus obtained solution was extracted with ethyl acetate (2×300 ml) and the combined organic layers were extracted with 2N hydrochloric acid (100 ml). Subsequently, the pH of the aqueous layer was adjusted to 12 with 2 N sodium hydroxide. Extraction with ethyl acetate (300 ml) then afforded an organic layer, which was washed with brine (100 ml), dried (magnesium sulphate) and concentrated under reduced pressure to give 1-amino-6-methoxyisoquinoline (11 g, 75%), ESI-MS: 175.2 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[C:25]1([CH:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:32][CH2:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][C:4]3([CH3:24])[CH2:8][C:7]4[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=4[O:5]3)[CH2:36][CH2:35]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Reactant: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCN1CCC(COC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 82 %

Procedure:
Using tert-butyl [2-(2-bromoethyl)-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate and 4-[(diphenylmethoxy)methyl]piperidine, the procedure of Reference Example 58 was otherwise repeated to provide the title compound. Yield 82%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15](C3CCCCO3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1.[OH-].[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:25][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
To a solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (46 mg, 0.137 mmol) in DCM (1 ml) was added DIPEA (0.119 ml, 0.684 mmol) and cyclopropyl carbonyl chloride (29 mg, 0.274 mmol). The reaction was stirred at room temperature for 1 hour, then 2M sodium hydroxide solution (2 ml) was added and the reaction stirred at room temperature for a further 1 hour. The organic layer was collected by passing through a hydrophobic frit. The aqueous layer was washed several times with DCM. The organic extracts were combined and solvent removed by blow down. The residue was dissolved in methanol (2 ml) and 4M HCl in 1,4-dioxane added (2 ml). The reaction was stirred at room temperature for 1 hour. The solvent was removed by blow down and the residue purified by mass directed preparative HPLC (method B). The residue was freeze dried to give the title compound as a pale brown solid (9 mg).