Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[NH:6][C:7]2[N:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[NH:18]([C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O)[NH2:19].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CO>[N:19]1[N:18]=[C:20]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[N:9]2[C:3]=1[C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[N:13]=[CH:12][CH:11]=[CH:10][C:8]2=1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CSC1=Nc2cccnc2Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 44.3 %

Procedure:
To a solution of 6-(methylthio)-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (2.5 g, 10.4 mmol) in dichloromethane (50 mL) and methanol (20 mL) was added the methyl 4-(hydrazinecarbonyl)benzoate (4.02 g, 20.7 mmol) followed by triethyl amine (1 mL) and p-toluenesulfonic acid monohydrate (3.3 g, 17.3 mmol). The reaction mixture was stirred at 70° C. for 20 hours. The mixture was partitioned between water (100 mL) and dichloromethane (150 mL). The phases were separated and the organic phase was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated from ethyl acetate, the solid filtered off and dried undet vacuum, yielding the methyl 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoate as a yellow solid (1.7 g, 44%). M.p.>300° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.83 (s, 1H), 8.23 (dd, J=4.8, 1.6 Hz, 1H), 8.02 (dt, J=8.8, 1.8 Hz, 2H), 7.97 (dd, J=8.0, 1.6 Hz, 1H), 7.58 (dt, J=8.8, 1.8 Hz, 2H), 7.45 (td, J=5.1, 1.6 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.2-7.1 (m, 2H), 6.91 (dd, J=8.4, 4.8 Hz, 1H), 3.88 (s, 3H); LCMS [M+H]: 370.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])=[N:6][CH:7]=1.B(O)(O)[C:16]1[CH:20]=[N:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[NH2:11][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[CH:3][C:2]([C:16]3[CH:20]=[N:19][N:18]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]4)[CH:17]=3)=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B(O)O)cn2)CC1
Reactant: Nc1cccc(-c2ncc(Br)cn2)c1
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(N)c4)nc3)cn2)CC1

Procedure:
A mixture of 3-(5-bromopyrimidin-2-yl)aniline (intermediate 4, 220 mg; 0.88 mmol; 1.0 eq.), 1-(1-Boc-piperidino)pyrazole-4-boronic acid (389 mg; 1.3 mmol; 1.5 eq.), Pd(PPh3)4 (51 mg; 0.04 mmol; 0.05 eq.) and K2CO3 (365 mg; 2.6 mmol; 3.0 eq.) in dioxane/water (3.3: 1.65 mL) was heated at 12000 for 30 min in a sealed tube in MW. The reaction mixture was then diluted with EtOAc. The two phases were separated and aqueous phase was extracted with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentrated. Flash chromatography on silica (EtOAc:heptane, gradient from 50:50 to 100:0) afforded the title compound a beige solid (240 mg; 65%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.52 (s, 1H), 8.11 (s, 1H), 7.67 (t, J=2.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.69-6.66 (m, 1H), 5.25 (s, 2H), 4.46-4.36 (m, 1H), 4.08-4.04 (m, 2H), 2.94 (m, 2H), 2.08-2.04 (m, 2H), 1.87-1.75 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 3.03 min (purity 99.0%). MS (ESI+): 421.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)=[N:24][CH:25]=1.C1(C(=O)CC(OC)=O)CC1.Cl.FC(F)(F)C1C=CC(C(N)=N)=CC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cn1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: COC(=O)CC(=O)C1CC1
Agent: Cl
Agent: N=C(N)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)nc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (prepared from methyl 3-cyclopropyl-3-oxopropanoate and 4-(trifluoromethyl)benzamidine hydrochloride, in analogy to the procedures described in examples 101C] to 101F]) to give 2-{4-[4-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as off-white crystalls of mp. 185.0–185.5° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:19])[CH3:18]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 56.3 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), acetyl chloride (0.055 mL, 0.69 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)acetamide (0.10 g). MS (ESI) m/z 258 ([M+H]+).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C(C3C=NN(CC(C)C)C=3)N=CC=4)=CC=2)CCC1.Cl[C:39]1[N:40]=[CH:41][CH:42]=[C:43]2[C:48](=[O:49])[C:47]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:59][CH2:58][CH2:57]4)=[CH:52][CH:51]=3)=[C:46]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[O:45][C:44]=12.[CH3:74][S:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=1B(O)O)(=[O:77])=[O:76]>>[CH3:74][S:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=1[C:39]1[N:40]=[CH:41][CH:42]=[C:43]2[C:48](=[O:49])[C:47]([C:50]3[CH:51]=[CH:52][C:53]([C:56]4([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:64])[CH3:65])[CH2:57][CH2:58][CH2:59]4)=[CH:54][CH:55]=3)=[C:46]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[O:45][C:44]=12)(=[O:77])=[O:76]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Agent: CC(C)Cn1cc(-c2nccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc23)cn1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5ccccc5S(C)(=O)=O)nccc4c3=O)cc2)CCC1
Yield: 62 %

Procedure:
Following the procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-8-(1-isobutyl-1H-pyrazol-4-yl)-2-phenyl-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl (1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl)carbamate was reacted with (2-(methylsulfonyl)phenyl)boronic acid to give the title compound (40 mg, 62%). LCMS (Method I): RT=7.31 min, [M+2]+=567 (-tBu).
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][CH2:2][NH:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(CCC(=O)OCc1ccccc1)NCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(CCC(=O)OCc1ccccc1)NCCl

Procedure:
A solution of 24.2 g. (0.10 mole) of benzyl N-hydroxymethylsuccinamate and 28.9 g. (0.11 mole) of triphenylphosphine in 500 ml. carbon tetrachloride is stirred at reflux for 12 hours. After filtering and washing the precipitate with benzene, the organic solvents are removed at 15 - 20 mm. and 30° - 40° C. to give benzyl N-chloromethylsuccinamate of sufficient purity for use in the next step.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].IC1C=CC(N2C(C)=CN=C2)=C(C=1)C#N>>[I:10][C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(I)ccc1F
Agent: Cc1cncn1-c1ccc(I)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(I)cc2C#N)cn1

Procedure:
As described for example 84a, 2-fluoro-5-iodo-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. Aqueous workup afforded a 1.9:1 mixture of the title compound and its regioisomer [5-iodo-2-(5-methyl-imidazol-1-yl)-benzonitrile] as a white solid (yield: 92%). MS: m/e=310.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11](=[C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]4=[CH:14][CH:15]=3)[NH:10][C:9](=[O:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S]>C(O)(=O)C>[C:1]1([C:7]2[C:16]3[C:11](=[C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]4=[CH:14][CH:15]=3)[NH:10][C:9](=[O:21])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)c2ccc3ccccc3c2N1
Agent: [S]
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2)c2ccc3ccccc3c2[nH]1
Temperature: 205 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
A mixture of 4-Phenyl-3,4-dihydro-1H-benzo[h]quinolin-2-one (0.55 g, 2.0 mmol) and sulfur (0.06 g, 2 mmol) was stirred at 205° C. for 0.5 hr under a nitrogen atmosphere. A second batch of sulfur (0.06 g, 2 mmol) was added and the solution stirred for 12 hr at 205° C. The product was dissolved in hot acetic acid and filtered. The clear filtrate upon cooling deposited crystals that were separated by filtration and washed with acetic acid and water followed by vacuum drying to afford the title compound (0.08 g, 0.30 mmol).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]4)=[CH:48][CH:47]=2)[CH:40]=[CH:41][CH:42]=1>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]4)=[CH:50][CH:51]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(OC)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: COc1cccc(NC(=O)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)O)C(C)C)C4=O)cc2)c1
Yield: 86 %

Procedure:
The compound of example 251 was prepared analogous to compound of example 225 by hydrolysis of compound of example 250.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH3:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:37])C(=O)C1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([Br:37])[CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH3:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)c2c1[nH]c1ccccc21
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a stirred solution of 3-(4-fluorobenzoyl)-1-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (compound in Example 32F) (110 mg, 0.28 mmol) in 6 mL of DCM was added NBS (48 mg, 0.27 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature under N2 for 1.5 hours and samples monitored by LC-MS. The solution was concentrated and purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (124 mg) as a yellow solid; 1H-NMR (CDCl3): δ 10.54 (1H, s), 7.98 (1H, d), 7.63 (2H, m), 7.50 (1H, d), 7.39 (1H, m), 7.16 (3H, m), 5.26 (1H, dd), 4.22 (2H, m), 3.78 (1H, m), 3.12 (1H, m), 1.28 (3H, d), 1.18 (3H, t). MS (ESI): 471, 473 (MH+).
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.I[C:19]1[NH:23][C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][O:25]2)=[N:21][C:20]=1[CH3:29].IC1NC(C)=NC=1C.[CH3:38][C:39]1[CH:48]=[C:47]([CH3:49])[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][C:40]=1[C:41]([O:43]C)=[O:42].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1>>[CH3:38][C:39]1[CH:48]=[C:47]([CH3:49])[C:46]([C:19]2[NH:23][C:22]([CH:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[N:21][C:20]=2[CH3:29])=[CH:45][C:40]=1[C:41]([OH:43])=[O:42]
Reactant: Cc1nc(C2CCCO2)[nH]c1I
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1cc(C)c(-c2[nH]c(C3CCCO3)nc2C)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazole (compound 173.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=1.C(O)(=O)C>O1CCOCC1.O>[CH3:19][S:18][C:14]1[N:15]=[C:16]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:12][N:13]=1
Reactant: CSc1nccc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CSc1nccc(OCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Benzyl alcohol (1.3 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.74 g) in 12.4 mL of dry dioxane, and the mixture was stirred at 100° C. for 30 min. A solution of 4-chloro-2-(methylthio)pyrimidine (2.0 g) in dry dioxane (8.2 mL) was added dropwise at 50° C. and the mixture was stirred at this temperature for 5 hours. After cooling at room temperature the mixture was acidified with glacial acetic acid, treated with water and extracted with dichloromethane. The organic phases were dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (70 g) eluting with ciclohexane/ethyl acetate from 95/5 to 9/1 to give the title compound as a white solid (1.22 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:10][C:9]=2[C:8]([O:20]C)=[CH:7][CH:6]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[OH:20][C:8]1[C:9]2[NH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][C:13]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccccc3)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
7-methoxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester (4.5 g, 15.94 mmol) obtained in step 3 was dissolved in 100 ml of toluene, aluminum chloride (9.56 g, 71.73 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (3.5 g, 13.77 mmol) in a yield of 86%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:34]([F:37])([F:36])[F:35])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:34]([F:37])([F:35])[F:36])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(OCC4CC4)c(C(F)(F)F)c3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(OCC4CC4)c(C(F)(F)F)c3)ccc12
Reaction time: 1 h
Yield: 8.8 %

Procedure:
To a solution of tert-butyl 2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (48.4 mg, 0.094 mmol) in DCM (1 mL) was added anisole (0.110 mL, 0.939 mmol) and TFA (0.209 mL, 2.82 mmol). The reaction mixture was stirred for 1 hour. The solvent was removed under vacuum. The residue was purified by preparative HPLC/MS to give the title compound as a solid (3.8 mg). LCMS m/z=460.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.29-0.38 (m, 2H), 0.50-0.61 (m, 2H), 1.14-1.28 (m, 1H), 2.14-2.26 (m, 1H), 2.53-2.61 (m, 1H), 2.63-2.72 (m, 1H), 2.72-2.83 (m, 1H), 3.52-3.61 (m, 1H), 3.89-4.03 (m, 3H), 4.04-4.16 (m, 1H), 5.06 (s, 2H), 6.01 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.06 (d, J=2.27 Hz, 1H), 7.18 (d, J=8.59 Hz, 1H), 7.24 (d, J=8.08 Hz, 1H), 7.61-7.72 (m, 2H), 12.27 (bs, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35]>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)c(F)c1
Yield: 39.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (800 mg, 2.6 mmoL) was reacted with tert-butyl 1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (1.4 g, 3.9 mmol) to afford the desired product (480 mg, 40%) as a brown solid: ESI MS m/z 469 [C25H2FN2O4S+H]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:26])=[O:2])=[CH:9][CH:8]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:25])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(-c2ncnc(C)c2C#Cc2ccc(N)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.2 g (6.3 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-benzoic acid methyl ester using 1.33 g (31.6 mmol.) LiOH in 5 mL water and 50 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and taken up in water. After freeze drying 2.7 g of crude product are obtained which is used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16])[CH:13]=1)[CH2:9]Br)=[C:3]([Cl:5])[Cl:4].[N-:19]=[N+:20]=[N-:21].[Na+]>C(O)C>[Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16])[CH:13]=1)[CH2:9][N:19]=[N+:20]=[N-:21])=[C:3]([Cl:5])[Cl:4]
Reactant: ClC(Cl)=C(Cl)c1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Yield: 97.6 %

Procedure:
A solution of crude 3,5-di(trichlorovinyl)benzyl bromide (7.9 g) and sodium azide (1.9 g) in 200 ml of ethanol was heated at reflux for 1.5 hours. The reaction mixture was concentrated and the residue partitioned between 100 ml of ether and 100 ml of water. The layers were separated and the aqueous phase further extracted with ether. The ethereal layers were washed with water, dried with MgSO4, and concentrated to give 7.03 g of an oil. This material was chromatographed on silica gel (hexane then 90:10 hexane:CH2Cl2) to give 3.52 g of pure azide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:31]1([CH2:38]I)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:38][CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ICC1CCCCCC1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CC1CCCCCC1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a stirred solution of (Benzhydrylidene-amino)-acetic acid tert-butyl ester (2.56 g; 8.68 mmol) in 30 mL of tetrahydrofuran under argon at −78° C. was added lithium diisopropylamide solution (10.0 mL; 1.5 M solution in cyclohexane) dropwise. After 30 minutes, a solution of cycloheptylmethyl iodide (Prepared in Step B; 3.48 g; 14.6 mmol) in 20 mL tetrahydrofuran was added dropwise and the mixture allowed to warm to room temperature and stirred for 18 h. The mixture was quenched with saturated ammonium chloride solution (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (sodium sulfate) filtered and concentrated in vacuo. The crude product was chromatographed (Biotage 40M; eluent: 5% ethyl acetate/hexanes) to give 2.56 g (73%) of 2-(Benzhydrylidene-amino)-3-cycloheptyl-propionic acid tert-butyl ester as a pale yellow oil.