Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24]1([C@@H:30]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:31]4[C@H:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:34][CH2:33][S:32]4(=[O:35])=[O:36])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=S1(=O)CC[C@@H](c2ccccc2)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](c5ccccc5)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 56.1 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and (S)-3-phenylisothiazolidine 1,1-dioxide (197 mg) described in Preparation Example 27 and by the reaction and treatment in the same manner as in Example 1, the title compound (275 mg) was obtained.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[OH:29][CH:30]([C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[C:31]([O:33][CH3:34])=[O:32]>>[OH:29][CH:30]([C:35]1[CH:36]=[CH:37][C:38]([C:2]2[N:7]3[CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:4][CH:3]=2)=[CH:39][CH:40]=1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: COC(=O)C(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Yield: 75.4 %

Procedure:
Compound 3a (350 mg, 0.760 mmol) was subjected to Suzuki coupling conditions with methyl 2-hydroxy-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (666 mg, 2.28 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 9c (300 mg, 72% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H29N5O4: 524.2 (M+H). Found 524.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:30][CH2:29][CH:28]([C:31](N)=[O:32])[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(OC1C=C(C2N=C(C3CCC(CO)CC3)N3C=CN=C(Cl)C=23)C=CC=1)C1C=CC=CC=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][OH:32])[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: NC(=O)C1CCC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)CC1
Agent: OCC1CCC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)CC1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](CO)CC1

Procedure:
trans-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol (compound of Formula I-B where Z=cyclohexyl and Q1=Ph-(3-OBn)) was prepared according to the procedures described for the synthesis of 4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide except for the substitution of trans-4-[1-(3-benzyloxyphenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]cyclohexane carboxylic acid methyl ester (compound of Formula II-A where Z=cyclohexyl, CO2A3=4-trans-CO2Me, and Q1=Ph-(3-OBn)) with {4-[1-(3-benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol (compound of Formula II-B where Z=cyclohexyl and Q1=Ph-(3-OBn)); 1H NMR (CDCl3, 400 MHz) δ 1.21 (ddd, 2H, J=25.2 Hz, 12.8 Hz, 3.6 Hz), 1.65-1.71 (m, 1H), 1.91 (ddd, 2H, J=29.6 Hz, 13.2 Hz, 3.6 Hz), 2.00-2.05 (m, 2H), 2.12-2.16 (m, 2H), 2.93 (tt, 1H, J=11.6 Hz, 4.0 Hz), 3.56 (d, 2H, J=6.0 Hz), 5.11 (bs, 2H), 5.16 (s, 2H), 7.05 (ddd, 1H, J=8.0 Hz, 2.8 Hz, 1.2 Hz), 7.07 (d, 1H, J=5.2 Hz), 7.20-7.22 (m, 2H), 7.23-7.24 (m, 2H), 7.31-7.35 (m, 1H), 7.36-7.41 (m, 2H), 7.42-7.45 (m, 2H); MS (ES) 429.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]([NH:13]C(=O)C(C)(C)C)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH2:8]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:13])=[N:5][CH:6]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCc1cnc(NC(=O)C(C)(C)C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCc1cnc(N)cc1C
Temperature: 100 °C

Procedure:
A suspension of 4-methyl-2-(trimethylacetyl)amino-5-(1-pentyl)-pyridine (233 mg, 0.89 mmol) in 2N hydrochloric acid (3 mL) was heated at 100° C. for 18 h. The solution was cooled to room temperature, made basic with 20% aqueous sodium carbonate and extracted with chloroform. The organic layer was dried (Na2SO4), and evaporated. The product was purified by silica gel column chromatography using 2% methanol/methylene chloride to give the title compound.
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:21])[CH3:20]
Reactant: CCOC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: CCOC1=C2C=c3c(cnn3CC(C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
2.05 g (7.2 mmol) of (RS)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 200 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 100 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 836 mg (7.2 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 2.35 g (87%) of (RS)-2-(7-ethoxy-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 191° were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]4[C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]4[C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4cccc(C(=O)OC)c4o3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4cccc(C(=O)O)c4o3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-benzoxazole-7-carboxylate obtained in Example (191a) (75 mg, 0.16 mmol) was dissolved in methanol (1 ml) and THF (1 ml). A 2 N aqueous lithium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration, washed with distilled water, and dried under reduced pressure at 50° C. to obtain the title compound as a solid.
Reaction SMILES: [Na][Na].O[CH:4]=[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6](=[O:16])[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:8]O.C1(CC(=O)CC2C=CC=CC=2)C=CC=CC=1.C(OCC)=O.C[O-].[Na+].CC(=O)C=C=C.C1(C2C(=O)C(C3C=CC=CC=3)=COC=2)C=CC=CC=1.O1C=CC=CC1=O.C([O-])(=O)C.[NH4+:83]>>[C:17]1([C:5]2[C:6](=[O:16])[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][NH:83][CH:4]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(C(=CO)c1ccccc1)C(=CO)c1ccccc1
Reactant: [NH4+]
Agent: C=C=CC(C)=O
Agent: CC(=O)[O-]
Agent: C[O-]
Solvent: CCOC=O
Product: O=c1c(-c2ccccc2)c[nH]cc1-c1ccccc1

Procedure:
The compounds of this invention can be prepared by various synthetic routes. Benary and Bitter, Ber. 61, 1058 (1928) taught the synthesis of an intermediate disodium salt of 1,5-dihydroxy-2,4-diphenyl-1,4-pentadien-3-one by the condensation of 1,3-diphenyl-2-propanone with ethyl formate in the presence of sodium methoxide. The intermediate pentadienone is neutralized by strong acid and forms 3,5-diphenyl-4-pyrone. Reaction of the pyrone with ammonium acetate at an elevated temperature produces 3,5-diphenyl-4(1H)-pyridone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH3:21])[CH3:2].[Br:23]Br.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:17][C:18]([Br:23])=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: CCOC(=O)COc1ccc(OCCc2cccs2)cc1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)COc1ccc(OCCc2ccc(Br)s2)cc1C
Reaction time: 0.25 h

Procedure:
A solution of ethyl[2-methyl-4-(2-thien-2-ylethoxy)phenoxy]acetate (intermediate 69, 0.306 g) in acetic acid (5 ml) was treated with bromine (0.180 g) at ambient temperature and the mixture stirred for 15 minutes. The mixture was poured into water and the resulting suspension extracted with diethyl ether. The organic layer was separated, dried over sodium sulfate and concentrated to give the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl.CCCCCC>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[Cl:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12)c1ccccc1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 2-chlorobenzoyl chloride. m.p.: 229-234° C. (dichloromethane/hexane)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:29](=[O:31])[CH3:30])=[CH:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 0 °C
Yield: 84.6 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg, 0.53 mmol) in THF (4 mL) was added triethylamine (65 mg, 90 μL, 0.64 mmol) and the resulting mixture cooled to 0° C. with ice. Then a solution of acetyl chloride (50 mg, 50 μL) in THF (1 mL) was added and the resulting mixture allowed to warm up to room temperature over 1 h. The mixture was then filtered and the filtrate evaporated before being diluted with methanol and potassium carbonate (10 mg) added. After one hour at room temperature the mixture was extracted with dichloromethane. The combined organic layers were then washed with water and then dried over sodium sulfate, filtered and evaporated to afford the title compound (145 mg, 84%) which was obtained as white crystals. MS: m/e=324.0 [M+H]+.
Reaction SMILES: C(N)C(C)(C)C.C(N(CC)C(C)C)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30](C)(C)[CH3:31])=[O:27])[CH:21]=[CH:20][C:19]=1[C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:42][S:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C@@H:53]([CH2:60][S:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:54][C:55]([N:57]([CH3:59])[CH3:58])=[O:56])=[C:48]([N+:68]([O-:70])=[O:69])[CH:47]=2)(=[O:45])=[O:44])=[O:41])=[CH:36][CH:35]=1>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][C:26](=[O:27])[NH:28][CH2:29][CH2:30][CH3:31])[CH:21]=[CH:20][C:19]=1[C:34]1[CH:35]=[CH:36][C:37]([C:40]([NH:42][S:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C@@H:53]([CH2:60][S:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH2:54][C:55]([N:57]([CH3:59])[CH3:58])=[O:56])=[C:48]([N+:68]([O-:70])=[O:69])[CH:47]=2)(=[O:45])=[O:44])=[O:41])=[CH:38][CH:39]=1
Reactant: COc1cc(CCC(=O)NCC(C)(C)C)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1
Agent: CC(C)(C)CN
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@@H](CSc4ccccc4)CC(=O)N(C)C)c([N+](=O)[O-])c3)cc2)c(OC)c1

Procedure:
The desired product was prepared by substituting propylamine hydrochloride for neopentylamine in Example 126 and adding N,N-diisopropylethylamine (0.1 mL) to the reaction mixture of Example 126D. MS (ESI(−)) m/e 760 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.81 (br t, 1H) 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.90 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.42 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.00-2.70 (m, 6H), 2.40 (t, 2H), 1.48 (m, 2H), 0.80 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[CH3:9][C:10]1([CH3:49])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:48])=[C:24]([NH:26][C:27]([C:29]2[N:33]3[CH:34]=[CH:35][C:36]([C:38]4[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:47])[CH:39]=4)=[CH:37][C:32]3=[N:31][CH:30]=2)=[O:28])[CH:25]=1)=[O:19]>>[CH3:9][C:10]1([CH3:49])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:48])=[C:24]([NH:26][C:27]([C:29]2[N:33]3[CH:34]=[CH:35][C:36]([C:38]4[CH:46]=[CH:45][C:41]([C:42](=[O:43])[NH:1][C@@H:2]5[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]5[OH:8])=[C:40]([F:47])[CH:39]=4)=[CH:37][C:32]3=[N:31][CH:30]=2)=[O:28])[CH:25]=1)=[O:19]
Reactant: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)N[C@@H]5CCCC[C@H]5O)c(F)c4)ccn23)c1

Procedure:
The title compound was prepared from (1R,2R)-2-aminocyclohexanol and 4-(3-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoic acid (step 3) analogously to Example 7.3 step 2;
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH:14]([CH2:26][CH3:27])[CH2:15][CH2:16][N:17](C)[C:18](=O)OC(C)(C)C)=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1)#[N:2].[ClH:28]>O1CCOCC1>[ClH:28].[CH2:26]([CH:14]([O:13][C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[C:6]([C:9]([F:12])([F:10])[F:11])[N:5]=1)[CH2:15][CH2:16][NH:17][CH3:18])[CH3:27]
Reactant: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1nc(C(F)(F)F)ccc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CCNC)Oc1nc(C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl [3-[[3-cyano-6-(trifluoromethyl)-2-pyridinyl]oxy]pentyl]methylcarbamate (170 mg) was dissolved in 4M HCl in dioxane (10 ml). The resulting solution was stirred at room temperature for 2 h, then the solvent was evaporated. The residue was recrystallised from diethyl ether/ethanol to give the title compound (100 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:22])[S@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(Cl)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H](c1cc(Cl)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of (S)-N-((R)-1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.6 mmol) in anhydrous THF (20 mL) under N2 atmosphere was dropwise added LHMDS (9.2 mL, 1 M in THF, 9.2 mmol) at −60° C. The reaction was stirred for 30 min at −60° C., followed by addition of MeI (1.04 g, 6.9 mmol). The reaction was stirred at room temperature for another 3 h and quenched with water at 0° C. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (1.2 g, yield: 76.5%); m/z (ES+): 342 [M+H]+.
Reaction SMILES: [C:1](OCC#N)(=[O:5])[CH2:2][CH:3]=[CH2:4].C([N+](CCCC)(CCCC)CCCC)CCC.[P:27]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][P:39]([O:42][CH2:43][C@@H:44]2[C@@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([N:51]3[CH:59]=[N:58][C:57]4[C:52]3=[N:53][CH:54]=[N:55][C:56]=4[NH2:60])[O:45]2)([OH:41])=[O:40])[CH2:36][C@H:35]([N:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[N:63][C:62]2=[O:68])[O:34]1)([OH:30])([OH:29])=[O:28].C(O)(C(F)(F)F)=O>CN(C=O)C>[C:1]([O:49][C@H:48]1[C@@H:47]([OH:50])[C@H:46]([N:51]2[CH:59]=[N:58][C:57]3[C:52]2=[N:53][CH:54]=[N:55][C:56]=3[NH2:60])[O:45][C@@H:44]1[CH2:43][O:42][P:39]([O:38][C@H:37]1[CH2:36][C@H:35]([N:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[N:63][C:62]2=[O:68])[O:34][C@@H:33]1[CH2:32][O:31][P:27]([OH:30])([OH:29])=[O:28])([OH:41])=[O:40])(=[O:5])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C=CCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanomethyl but-3-enoate (Compound 86) (0.050 g, 0.400 mmol) was added to a solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate tetrabutylammonium salt (Compound 1h) (0.20 g, 0.150 mmol) in DMF (1.0 ml), and the mixture was stirred at room temperature for 1 hour. A 0.05% aqueous TFA solution was added to the reaction solution, the mixture was lyophilized, and the resulting residue was purified by preparative HPLC (0.05% aqueous TFA solution:acetonitrile) to prepare the title compound 85 (0.010 g, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=1)[CH:7]=[C:6]2[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[C:42](Cl)(=[O:58])[O:43][CH2:44][CH:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[C:8]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)[CH:7]=[C:6]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:42]([O:43][CH2:44][CH:45]3[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:51]=4[C:52]4[C:57]3=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:58])[CH2:24][CH2:23]2)=[CH:11][CH:12]=1
Reactant: CNc1nccc(-c2cc(NC3CCNCC3)c3cc(OC)ccc3c2)n1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nccc(-c2cc(NC3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 4-(6-methoxy-4-(piperidin-4-ylamino)naphthalen-2-yl)-N-methylpyrimidin-2-amine 150 (0.46 g, 1.32 mmol), N,N-diisopropylethylamine (0.92 mL, 5.2 mmol), N,N-dimethylformamide (2 mL), and tetrahydrofuran (10 mL), (9H-fluoren-9-yl)methyl carbonochloridate (0.41 g, 1.6 mmol) was added. The reaction was stirred at room temperature for 30 min and then partitioned between water (100 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated (rotary). The residue was purified by column chromatography (silica gel) using 60% ethyl acetate/hexanes as the eluent to afford (9H-fluoren-9-yl)methyl 4-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)piperidine-1-carboxylate 205 as a yellow solid (0.53 g). LC/MS (m/z): 586 [M+H].
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([NH2:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:14]([O:18][C:19](=[O:36])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OCC(C)(C)CO2)=[CH:24][N:23]=1)([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:14]([O:18][C:19](=[O:36])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([C:11](=[O:12])[NH2:13])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:24][N:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC1(C)COB(c2ccc(CNC(=O)OC(C)(C)C)nc2)OC1
Reactant: NC(=O)c1ccc2nc(Cl)sc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccc(C(N)=O)cc3s2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A mixture of 2-chloro-1,3-benzothiazole-6-carboxamide (77 mg, 0.36 mmol), tert-butyl[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-2-yl]methylcarbamate (0.174 g, 0.54 mmol), Pd(dppf)Cl2*DCM (30 mg, 0.036 mmol) and 2 M aq. K2CO3 (0.8 mL) in DMF (2 mL) was stirred under argon at 80° C. for 2 h. The reaction mixture was filtered and the filtrate was partitioned between EtOAc and H2O. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (Heptane/EtOAc gradient) gave the product (66 mg) as a white solid. MS m/z (M−H) 383.
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(C)CCN(C)C.[Li]CCCC.[CH3:29][C:30](OC(C)=O)=[O:31]>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[C:30](=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCc1sc2ccccc2c1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1c(CCN(C)C)sc2ccccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 50.4 %

Procedure:
Compound 2a, [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (17.5 mmol), was dissolved in anhydrous toluene (180 mL) and cooled to −78° C. Tetramethylethylenediamine (17.5 mmol) was added followed by n-BuLi (21.0 mmol, 1.6 M in hexanes). The mixture was stirred for 45 min at −78° C. Ac2O (70 mmol) was added and the mixture was allowed to slowly reach RT and was stirred overnight. The mixture was quenched with sat. NH4Cl, the pH of the aqueous layer was adjusted to 7-8 with sat. NaHCO3, and the reaction mixture was extracted with EtOAc (4×). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography in CH2Cl2 with a gradient up to CH2Cl2/MeOH=94/6 to afford Compound 6a, 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-ethanone (2.18 g, 50%); MS (MH+)=248.1.