Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:73])/[C:40](/[C:48]2[N:49]=[C:50]([C:54]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[S:51][C:52]=2[NH2:53])=[N:41]\[O:42]C(OC)(C)C)[C:19]3=[O:74])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>CC(C)=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:73])/[C:40](/[C:48]2[N:49]=[C:50]([C:54]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[S:51][C:52]=2[NH2:53])=[N:41]\[OH:42])[C:19]3=[O:74])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)sc1N
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5nc(C(c6ccccc6)(c6ccccc6)c6ccccc6)sc5N)[C@H]4SC3)sc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75.8 %

Procedure:
To a solution of the product obtained in Step 3 (1.5 g) in acetone (12 ml) was added 1 N hydrochloric acid (2.6 ml), and the resulting solution was stirred at room temperature for 3.5 hours. Ethyl acetate was added to the solution, and the organic layer was washed with water, 5% sodium bicarbonate solution and brine in that order, and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 1.06 g of the objective compound as milky white crystals.
Reaction SMILES: [CH3:1][C:2]([OH:15])([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)[CH3:3].[H][H]>C(O)(C)C>[CH3:3][C:2]([OH:15])([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)[CH3:1]
Reactant: CC(C)(O)C#Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CC(C)O
Product: CC(C)(O)C#Cc1cccc(N)c1
Yield: 76.7 %

Procedure:
20 grams of 2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol in 250 grams of isopropanol was hydrogenated in the presence of a cobalt polysulfide paste prepared as above for 1.25 hours at 110° C. and 1000 psig (6.9 MPa) of hydrogen pressure. After filtration, and evaporation of the solvent, the residue was crystallized from toluene to give 13.1 grams (77% yield, recovered) of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol, melting point 117° to 120° C.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH2:11][N:10]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:9][CH2:8]2.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([S:39](Cl)(=[O:41])=[O:40])[C:34]([F:38])=[CH:35][C:36]=1[F:37]>C(Cl)Cl>[Cl:30][C:31]1[C:36]([F:37])=[CH:35][C:34]([F:38])=[C:33]([S:39]([NH:20][CH2:19][CH2:18][CH2:17][N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH3:3])[CH:6]=3)[CH2:11]2)(=[O:41])=[O:40])[CH:32]=1
Reactant: COc1cc2c(cc1OC)CN(CCCN)CC2
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)CN(CCCNS(=O)(=O)c1cc(Cl)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of 3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propylamine dihydrochloride (323 mg, 1 mmol), N,N-diisopropylethylamine (517 mg, 4 mmol) in CH2Cl2(15 mL), was added 3-Chloro-4,6-difluorobenzenesulfonyl chloride (259 mg, 1.05 mmol) and was stirred overnight at room temperature. The resulting solution was washed with water (3×20 mL) and dried over Na2SO4, and evaporated to dryness. The free base was dissolved in 2-propanol (5 mL). The product was crystallized in 2-propanol (5 mL) collected by filtration, and vacuum dried to give a white solid (401 mg, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[CH3:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]4)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1ccc2c(Cl)ccnc2c1
Product: COc1ccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2c1
Yield: 65.9 %

Procedure:
The title compound (1.73 g, 66% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4-chloro-7-methoxyquinoline (1.77 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 346 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][C:11](=[O:17])[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC=CC=1>[C:1]1([C:7]2[O:8][C:9]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:10][C:11](=[O:17])[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)C1=C(c2ccccc2)OC(c2ccccc2)CC1=O
Solvent: c1ccccc1
Product: CNC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O

Procedure:
A mixture of 10.0 grams (0.0324 mole) of 5,6-dihydro-2,6-diphenyl-N-methyl-4-oxo-4H-pyran-3-carboxamide, 11.0 grams (0.0485 mole) of dichloro dicyanoquinone and 200 milliliters of benzene is refluxed for 18 hours. The mixture is cooled and the precipitate filtered and washed with benzene and methylenedichloride. The filtrate is evaporated to dryness and the residue is partitioned between methylenedichloride and 2N sodium hydroxide and the layers separated. The organic layer is washed with 2N sodium hydroxide, water and 50 percent brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is dissolved in a hot 50:50 mixture of ethanol:methanol, treated with decolorizing charcoal, filtered and evaporated in vacuo. The residue is crystallized from ethanol to give 2,6-diphenyl-N-methyl-4-oxo-4H-pyran-3-carboxamide, m.p. 196° C. - 197° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=O)[CH:27]=2)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:27]=2)[CH:22]=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc2cc[nH]c2c1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5cc[nH]c5c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-6-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-6-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8]C2OC(C3C=CC(C#N)=CC=3)=CN=2)[CH:7]=1.Cl[C:24]1[O:25][C:26]([C:30]2[CH:37]=[C:36]([CH3:38])[C:33]([C:34]#[N:35])=[C:32]([CH3:39])[CH:31]=2)=[C:27]([Cl:29])[N:28]=1.ClC1OC(C2C=CC(C#N)=CC=2)=CN=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:24]2[O:25][C:26]([C:30]3[CH:37]=[C:36]([CH3:38])[C:33]([C:34]#[N:35])=[C:32]([CH3:39])[CH:31]=3)=[C:27]([Cl:29])[N:28]=2)[CH:7]=1
Reactant: Cc1cc(-c2oc(Cl)nc2Cl)cc(C)c1C#N
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Agent: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Product: Cc1ccc(N)cc1Nc1nc(Cl)c(-c2cc(C)c(C#N)c(C)c2)o1
Yield: 74 %

Procedure:
The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However 4-(2,4-dichlorooxazol-5-yl)-2,6-dimethylbenzonitrile was used instead 4-(2-Chloro-oxazol-5-yl)-benzonitrile. Yield=74%.
Reaction SMILES: COC(C[O:6][C:7](=[O:21])[CH:8]([NH:17][C:18](=[O:20])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=O.Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[C:18]([NH:17][CH:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:15]=1)[C:7]([OH:6])=[O:21])(=[O:20])[CH3:19]
Reactant: COC(=O)COC(=O)C(Cc1ccc(O)cc1)NC(C)=O
Reactant: COC(=O)CCl
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(NC(C)=O)C(=O)O)cc1

Procedure:
To mixture of 2-Acetylamino-3-(4-hydroxy-phenyl)-propionic acid methoxycarbonylmethyl ester 5 (5 grams, 16.95 mmol) Potassium carbonate (9.4 grams, 68 mmol) sodium iodide (1 gram, 6.67 mmol) Disodium Phosphate (1 gram, 70.84 mmol) in acetone (50 mL) is added Methyl chloroacetate (2.2 grams, 20.27 mmol) and is refluxed till the reaction complies by TLC. Acetone is distilled, water is added and the crude 6 can be extracted into chloroform, dried over sodium sulphate and distilled.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][CH2:10][C:11]([N:13]([C@H:15]([CH3:37])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:14])=[O:12]>>[OH:9][CH2:10][C:11]([N:13]([CH3:14])[C@H:15]([CH3:37])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)=[O:12]
Reactant: Cc1cc(Nc2ncnc3cccc(OC[C@@H](C)N(C)C(=O)CO)c23)ccc1O
Reactant: ClCc1ccccn1
Product: Cc1cc(Nc2ncnc3cccc(OC[C@@H](C)N(C)C(=O)CO)c23)ccc1OCc1ccccn1
Yield: 15 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-N-[(1R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide to give the title compound as a white solid in 15% yield; NMR spectrum (DMSO-d6 373K) 1.25 (d, 3H), 2.28 (s, 3H), 2.83 (s, 3H), 3.96 (s, 2H), 4.35 (m, 1H), 4.46 (t, 1H), 4.97 (m, 1H), 5.19 (s, 2H), 7.01 (d, 1H), 7.18 (d, 2H), 7.33 (m, 2H), 7.44 (m, 1H), 7.56 (d, 1H), 7.68 (t, 1H), 7.83 (td, 1H), 8.40 (s, 1H), 8.58 (d, 1H), 9.48 (s, 1H); Mass spectrum MH+ 488.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].C1([Mg]Br)C=CC=CC=1>>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc([Si](C)(C)C)cc2)C[C@@H]2CC[C@H]1N2C
Agent: Br[Mg]c1ccccc1
Product: COC(=O)[C@H]1[C@@H](c2ccccc2)C[C@@H]2CC[C@H]1N2C

Procedure:
This compound was synthesized using a similar reaction as 2β-Carbomethoxy-3β-(4′-trimethylsilylphenyl)tropane starting with anhydroecognine methyl ester and phenylmagnesium bromide.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]2[N:13]=[C:14]3[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:18][CH:17]=[C:16]([C:26]4[CH:27]=[CH:28][C:29]([N:32]5[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)=[O:39])[CH2:34][CH2:33]5)=[N:30][CH:31]=4)[N:15]3[CH:48]=2)[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].ClC1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[N:57]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.O>[O:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:14]3[N:15]([CH:48]=[C:12]([CH:10]4[CH2:9][N:8]([C:6]5[CH:65]=[CH:64][C:63]6[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=6)[N:57]=5)[CH2:11]4)[N:13]=3)[C:16]([C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:39])[CH2:34][CH2:33]4)=[N:30][CH:31]=3)=[CH:17][N:18]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3c(-c4ccc(N5CCN(C(=O)OCc6ccccc6)CC5)nc4)cnc(N4CCOCC4)c3n2)C1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(C5CN(c6ccc7ccccc7n6)C5)cn34)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 29c (275 mg, 0.420 mmol) in DCM (3 mL), TFA (2 mL) was added. The resulting mixture was stirred at rt for 2 h and concentrated. The residue obtained was dried under reduced pressure overnight and re-dissolved in EtOH (5 mL). Na2CO3 (1.00 g, 9.50 mmol) and 2-chloroquinoline (234 mg, 1.43 mmol) were then added and the resulting mixture was heated at reflux for 5 h. The reaction mixture was allowed to cool to rt, diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtOA/heptane) to obtain compound 29d. Mass Spectrum (LCMS, ESI pos.) Calcd. for C39H39N9O3: 682.3 (M+H). Found 682.3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[S:6].[CH:7]1([CH:10]([NH2:14])[CH:11]2[CH2:13][CH2:12]2)[CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([CH:10]([NH:14][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[S:6])[CH:11]2[CH2:13][CH2:12]2)[CH2:9][CH2:8]1
Reactant: S=C=NCCCl
Reactant: NC(C1CC1)C1CC1
Solvent: C1CCOC1
Product: S=C(NCCCl)NC(C1CC1)C1CC1
Temperature: 25 °C

Procedure:
9.2 g of β-chloroethyl isothiocyanate dissolved in 20 ml tetrahydrofuran are added dropwise to a solution of 9 g of dicyclopropylmethylamine in 70 ml tetrahydrofuran. The reaction mixture is kept at a temperature of from 0° to +5° C. during the addition, then maintained at room temperature for 2 hours. The solvent is evaporated to dryness and the residue, consisting essentially of N-(1,1-dicyclopropylmethyl) N'-(β-chloroethyl) thiourea, is recovered and used without any further purification for the next step of the synthesis.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[CH2:62][NH:63][S:64]([CH3:67])(=[O:66])=[O:65]>CN1C(=O)CCC1>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:49])[CH2:62][NH:63][S:64]([CH3:67])(=[O:66])=[O:65])=[CH:73][CH:72]=1
Reactant: CS(=O)(=O)NCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CNS(C)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 79.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (88 mg, 0.23 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (79 mg, 0.22 mmol) and N-ethyldiisopropylamine (0.046 mL, 0.26 mmol) in NMP (3 mL). The mixture was treated with N-(2-amino-2-(4-chlorophenyl)ethyl)methanesulfonamide (Intermediate 75) (60 mg, 0.24 mmol). The solution was stirred for 65 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water. The organic solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(1-(4-chlorophenyl)-2-(methylsulfonamido)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (103 mg, 79%) as colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:59][CH2:58][N:57]3[C:50](=[CH:51][C:52]4[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55][C:56]=43)[C:49]2=[O:62])=[N:35][CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1)(=[O:30])[CH3:29].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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(#N)C.O>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:59][CH2:58][N:57]3[C:50](=[CH:51][C:52]4[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55][C:56]=43)[C:49]2=[O:62])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: C[C@H]1CN(C2COC2)CCN1c1cnc(Nc2cc(Br)cn(C)c2=O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 65 °C
Yield: 30.7 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (S)-5-bromo-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrazin-2-ylamino)pyridin-2(1H)-one 230f (200 mg, 0.46 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]-dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (366 mg, 0.92 mmol), Pd(dppf)Cl2 (38 mg, 0.046 mmol), sodium acetate (126 mg, 0.92 mmol), K3PO4 (196 mg, 0.92 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 65° C. for 3 hrs. After cooling to room temperature the reaction was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 235a as brown solid (100 mg, 31%). MS-ESI: [M+H]+ 708.5.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2.[OH:21]O.[OH-].[Na+]>CO.O>[O:21]1[C:10]23[C@:15]([CH3:16])([CH2:14][CH2:13][C:12](=[O:20])[C@H:11]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[CH2:3][CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@]12CCC[C@H]1[C@@H]1CCC34O[C@H]3C(=O)CC[C@]4(C)[C@H]1CC2
Temperature: 3 °C

Procedure:
4-Androstene-3-one (4.3g) is dissolved in 300ml of methanol and cooled to 3° C in an ice-water bath. To the cooled mixture is added 20ml of 30% hydrogen peroxide and 26ml of 4N sodium hydroxide solution simultaneously from 2 dropping funnels. The addition is carried out in a nitrogen atmosphere with stirring. The mixture is allowed to warm to room temperature and stirring is continued for an additional hour. The mixture is diluted with 4 liters of water and extracted with methylene chloride. The organic layer is dried over sodium sulfate and concentrated to yield 3.0g of the title compound.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.Cl>O1CCCC1>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([CH2:20][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:26][CH:25]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
A solution of tert-butyl acetoacetate (7.2 g) in tetrahydrofuran (80 ml) was added to a stirred solution of sodium hydride (1.33 g) in tetrahydrofuran (60 ml) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 10 minutes followed by the addition of n-butyl lithium (23 ml, 2.5 M solution in hexane) dropwise over 10 minutes. The resulting reaction mixture was stirred for 10 minutes. A solution of 4-(bromomethyl) biphenyl (12.5 g) in tetrahydrofuran (60 ml) was added over 10 minutes and the resulting solution was stirred at 0° C. for approximately 2 hours. To resulting mixture was added hydrochloric acid (6 M, 15 ml) followed by extracting the mixture with diethyl ether. The organic layers were combined, washed with water and brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography using 8% ethyl acetate-hexane as eluant to furnish the title compound (7.5 g).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[C:13]3[C:8]2=[C:9]([CH3:21])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.Cl.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][O:20][C:15]1[C:14]2[C:13]3[C:8](=[C:9]([CH3:21])[CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH3:26]
Reactant: Cc1cccc2c3c(O)cccc3n(Cc3ccc(F)cc3)c12
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cccc(C)c1n2Cc1ccc(F)cc1
Yield: 63.1 %

Procedure:
9-(4-Fluorobenzyl)-8-methyl-9H-carbazol-4-ol (0.0176 g, 0.058mmol), 2-diethylaminoethylchloride hydrochloride (0.0144 g, 0.084 mmol), potassium carbonate (0.0332 g, 0.24 mmol), sodium iodide (0.0008 g, 0.0053 mmol) and DMF (1 mL) are heated at 85° C. for 4 h. After the mixture had cooled, it is partitioned between water and ethyl acetate. The aqueous layer is also washed with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (10 mL) using methanol/dichloromethane (1/99 and 2/98) to give 0.0148 g (55%) of the title compound; MS (ESI+) for C26H29FN2O m/z 405.2 (M+H)+; 1H NMR (CDCl3) δ1.23, 2.65, 2.88, 3.26, 4.47, 5.75, 6.73, 6.95, 7.15, 7.33, 8.29. Anal. Calcd for C26H29FN2O: C, 77.20; H, 7.22; N, 6.93. Found: C, 73.47; H, 7.06; N, 6.53.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13]([CH2:15][C:16]([O:18]CC)=O)=[N:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[C:30]#[N:31]>C1COCC1>[NH2:31][C:30]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[NH:23][C:16](=[O:18])[C:15]=1[C:13]1[NH:12][C:11]2[CH:21]=[CH:22][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:9][C:10]=2[N:14]=1
Reactant: CCOC(=O)Cc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Reactant: N#Cc1ccncc1N
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3[nH]c(-c4c(N)c5ccncc5[nH]c4=O)nc3c2)CC1
Reaction time: 8 h

Procedure:
LIHMDS (3.6 eq) was added to ethyl [5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and 3-aminopyridine4-carbonitrile (1.0 eq) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a green solid. The crude material was washed successively with CH2Cl2 and MeOH and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 376.3 (MH+), Rt 1.70 minutes.