Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Li+].CC([N-]C(C)C)C.[S:14]1[C:18]2[C:19]([C:22]([OH:24])=[O:23])=[CH:20][S:21][C:17]=2[N:16]=[N:15]1.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:25][C:20]1[S:21][C:17]2[N:16]=[N:15][S:14][C:18]=2[C:19]=1[C:22]([OH:24])=[O:23]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1csc2nnsc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)sc2nnsc12
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
79 ml (201.6 mmol) of n-butyllithium (1.6M in hexane) are added at -30° C., under nitrogen, to a solution of 20.4 g (201.6 mmol) of diusopropylamine in 200 ml of tetrahydrofuran (THF). After 20 minutes' stirring at -20° C., the LDA solution so prepared is added dropwise at -90° C., under nitrogen, by means of a capillary, to a suspension of 15.0 g (80.6 mmol) of thieno[2,3-d]1,2,3-thiadiazole-6-carboxylic acid in 150 ml of THF. After 90 minutes' stirring at -50° C., a solution of 42.0 g (177.2 mmol) of hexachloroethane in 70 ml of THF is added at -90° C. and the reaction mixture is heated to room temperature within a period of 2 hours. Then the reaction mixture is poured onto 2 litres of water, the aqueous phase is extracted with diethyl ether and acidified with concentrated hydrochloric acid, and the product is isolated by filtration. There are obtained 17.55 g of light-brown solid having a melting point of 255°-265° C. (decomposition).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](I)=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:23]([O:27][C:28](=[O:47])[N:29]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[C:32]([F:38])[N:31]=1)([CH3:26])([CH3:25])[CH3:24].O>O1CCCC1>[C:23]([O:27][C:28](=[O:47])[N:29]([C:30]1[C:35]([CH3:34])=[C:36]([OH:37])[C:33]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:6]([Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:7]=2)=[C:32]([F:38])[N:31]=1)[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)c(F)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N(Cc2ccc(Cl)cc2)C(=O)OC(C)(C)C)nc(F)c(-c2cn([Si](C)(C)C(C)(C)C)c3ncccc23)c1O
Temperature: 0 °C

Procedure:
To 1-(tert-butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (66, 0.53 g, 0.0015 mol) and tetrahydrofuran (15.0 mL), under an atmosphere of nitrogen at −20° C., was added isopropylmagnesium chloride (0.78 mL, 2.0 M in tetrahydrofuran). The reaction was allowed to warm to 0° C. (around 80 minutes), then cooled to −20° C., followed by addition of (4-Chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (65, 0.200 g, 0.55 mmol) in tetrahydrofuran (6.0 mL). The reaction was allowed to warm to room temperature in 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a yellow solid (67, 0.20 g, 61.1%). MS (ESI) [M+H+]+=597.4.
Reaction SMILES: [C:1]1([S:7](Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C@:13]1(O)[C:18](=[CH2:19])[CH2:17][C@H:16]2[C@H:20]3[C:30](=[CH:31][CH2:32][C@:14]12[CH3:15])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH:26]=[CH:27]1)[CH2:22][CH2:21]3)(=[O:12])[CH3:11].P([O-])([O-])([O-])=O>C(Cl)Cl.C(N(CC)CC)C>[C:1]1([S:7]([CH2:19][C:18]2[CH2:17][C@@H:16]3[C@:14]([CH3:15])([CH2:32][CH:31]=[C:30]4[C@H:20]3[CH2:21][CH2:22][C:23]3[C@:28]4([CH3:29])[CH:27]=[CH:26][C:25](=[O:33])[CH:24]=3)[C:13]=2[C:10](=[O:12])[CH3:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)c1ccccc1
Reactant: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C1=C(CS(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C

Procedure:
Phenylsulfinyl chloride in methylene chloride (2.5N, 2.4 ml) was added to a mixture of 17α-acetyl-17β-hydroxy-16-methyleneandrost-1,4,9(11)-trien-3-one (VB, Example 17, 1 g) in methylene chloride (10 ml) and triethylamine (0.82 ml) previously cooled to -30° over a period of 2 hrs. The reaction is plunged into phosphate buffer (pH 7, 10 ml); the phases are separated; the aqueous phase is extracted with methylene chloride; the organic phases are combined and dried over sodium sulfate and concentrated under reduced presure to an isomeric mixture of the title compound. The isomers are separated by chromatography on silica gel (50 g), eluting with acetone/hexane: 5/95 to give the title compound, NMR (CDCl3) 0.89, 1.42, 2.10, 4.03, 5.5, 6.0, 6.27, 7.20 δ.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH2:23]([NH:25][CH3:26])[CH3:24]>>[CH2:23]([N:25]([CH3:26])[C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:22])[F:21])=[N:4]2)=[CH:20][CH:19]=1)[CH3:24]
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CCNC
Product: CCN(C)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid and N-ethylmethylamine using a similar procedure to that described for Example 2.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[OH:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][C:27](=[O:33])[NH:28]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:26]3[C:25]4[C:29](=[CH:30][CH:31]=[CH:32][C:24]=4[CH2:23][CH2:22][OH:21])[NH:28][C:27]3=[O:33])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(CCO)c43)c(C)c2C1=O
Yield: 35 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (prepared according to US2004186160) as starting materials to give 5-(2-diethylamino-ethyl)-2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 35.0%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[F:15][CH:16]([F:37])[O:17][C:18]1[CH:19]=[C:20]2[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[C:21]2=[N:22][CH:23]=1.[H-].[Na+]>CN(C=O)C>[F:37][CH:16]([F:15])[O:17][C:18]1[CH:19]=[C:20]2[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:32][CH:31]=3)[C:21]2=[N:22][CH:23]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OC(F)F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(OC(F)F)cc21
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (62 mg) and 6-(difluoromethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (86 mg) in DMF (3 mL) was added NaH (13 mg) at room temperature, and the mixture was stirred at 180° C. under microwave irradiation for 30 min. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, NH silica gel, eluted with 50%-100% AcOEt in hexane) and recrystallized from AcOEt/hexane to give 6-(difluoromethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (56 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=[O:30])[CH3:25])[C:16]=1[CH3:35])=[O:14].[CH3:36]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([O:31][CH3:36])=[O:30])[CH3:25])[C:16]=1[CH3:35])=[O:14]
Reactant: CO
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)c2cccc(C(=O)O)c2)c2ncccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(C)n2c(C)c(C(=O)NCc3c(OC)cc(C)[nH]c3=O)c3cccnc32)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 3-(1-(3-(((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)benzoic acid (20 mg, 0.042 mmol) in MeOH (6 mL) was added 2-3 drops of sulfuric acid. The mixture was stirred at 70° C. for 1 hour. The solvent was evaporated. The residue was dissolved in water (3 mL), quenched by saturated NaHCO3 solution, extracted with EA (10×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated to give the title compound (20 mg, yield: 97%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:16](=[O:19])[NH:17][N:18]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[CH:9]=2.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:15][C:10]1[CH:9]=[C:8]2[C:13]([N:14]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[C:6]3[N:7]2[C:16](=[O:19])[NH:17][N:18]=3)=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NCCNc1nc2ccc(F)cc2n2c(=O)[nH]nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=c1[nH]nc2c(NCCNc3ccc(C(F)(F)F)cn3)nc3ccc(F)cc3n12
Temperature: 25 °C

Procedure:
A solution of 259 mg of 4-(2-amino-ethylamino)-8-fluoro-2H-[1,2,4]triazolo[4,3-a]quinoxalin-1-one, 422 mg of 2-chloro-5-trifluoromethylpyridine and 411 mg of sodium carbonate in n-butanol (1 mL) was heated to reflux for 48 hrs. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate concentrated to give a solid residue. This was separated by silica gel chromatography to provide the title compound. MS (M+H)+=407.9.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[C:11]([CH3:17])[CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:11]([CH3:17])[CH:10]=1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1Cn1ccnc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF was treated with NaH (20.0 mg, 0.86 mmol) and heated to 90° C. After lh a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138, 190.0 mg, 0.72 mmol) in 3 mL DMF was added and stirring at 90° C. continued for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 160.0 mg (88%) was isolated by column chromatography (5% MeOH-EtOAc) as a colorless solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH2:9][CH:8]=[C:7]2[CH2:15][C:16]([O:18]C)=O.C[OH:21]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:21])[CH:8]=[C:7]2[CH2:15][CH2:16][OH:18]
Reactant: COC(=O)CC1=CCN(C)c2ccc(Cl)cc21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)cc(CCO)c2cc(Cl)ccc21

Procedure:
3.0 g (79 mmol) of sodium borohydride are added to a suspension of 5.9 g (23.4 mmol) of methyl 6-chloro-1-methyl-1,2-dihydro-4-quinolineacetate in 10 ml of methanol and 100 ml of dry tetrahydrofuran, and the mixture is then heated to reflux for 9 hours. After cooling, the solvents are evaporated off under vacuum and the residue is taken up in 400 ml of dichloromethane and 100 ml of 3 N hydrochloric acid. The organic phase is washed with water, dried over sodium sulphate and filtered and the filtrate is condensed. The crude product is purified by flash chromatography on silica, eluting with a methanol/dichloromethane (5:95) mixture.
Reaction SMILES: [F:1][C:2]1[C:16](I)=[CH:15][C:5]([O:6][C:7]2[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.[C:21]([C:23]1C(F)=CC(C(C)C)=C(C=1)OC1C(N)=NC(N)=NC=1)#[CH:22]>>[F:1][C:2]1[C:16]([C:22]#[C:21][CH3:23])=[CH:15][C:5]([O:6][C:7]2[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: C#Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1F
Reactant: CC(C)c1cc(F)c(I)cc1Oc1cnc(N)nc1N
Product: CC#Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1F

Procedure:
Similarly prepared from 5-(4-fluoro-5-iodo-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine using the procedure of step 8 of example 1 was 5-(5-Ethynyl-4-fluoro-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine, MS (M+H)=289.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:34])=O)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:44][C@@H:45]1[NH:50][CH2:49][CH2:48][N:47]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:46]1>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([N:50]2[CH2:49][CH2:48][N:47]([S:51]([C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=3)(=[O:52])=[O:53])[CH2:46][C@@H:45]2[CH3:44])=[O:34])[CH:27]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
HATU (411 mg, 1.08 mmol) was added to a solution of 4-chloro-2-pyridinecarboxylic acid (142 mg, 0.90 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.394 ml, 2.25 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (333 mg, 1.082 mmol) was then added and stirring was continued for 1.5 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organics were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave a pale yellow gum, shown to be impure by LCMS and NMR analysis. Further purification by MDAP gave the title compound as a colourless glass (159 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[C:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[C:45]([O:47][CH3:48])[CH:46]=1)#[N:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:48][O:47][C:45]1[CH:46]=[C:41]([CH:42]=[C:43]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:44]=1)[C:39]#[N:40]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(C#N)cc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(C#N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 43 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (3-cyano-5-methoxyphenyl)boronic acid (74 mg, 0.42 mmol), sodium carbonate (45 mg, 0.42 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41 mg, 0.05 mmol) and 4 ml 1,2-dimethoxyethane and 1 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 54 mg (43% yield, 87% purity) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.[CH3:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[S:53]([NH2:56])(=[O:55])=[O:54]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:28])([F:30])[F:29])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([NH:56][S:53]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH3:46])(=[O:54])=[O:55])=[O:8]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Yield: 56.8 %

Procedure:
A solution of 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoic acid (250 mg), 4-dimethylaminopyridine (69.8 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg) and 2-methylbenzenesulfonamide (95.4 mg) in methylene chloride (5 mL) was stirred under a nitrogen atmosphere for 24 hours. The mixture was diluted with methylene chloride, washed (10% (w/v) hydrochloric acid, water), and evaporated. The resulting rose-colored foam was dissolved in methylene chloride (5 mL), filtered through a 0.45 micron membrane filter, and precipitated by addition to hexane (50 mL). The solid was collected by filtration to give the title compound (189.2 mg, 57%) as a pale pink powder; mp 147°-149 ° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12](=[S:14])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](OC(OCC)([O-])CBr)[CH3:25]>C(COC)OC>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11][C:12]1[S:14][CH:24]=[CH:25][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=S)C(=O)OCc1ccccc1
Reactant: CCOC([O-])(CBr)OCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)OCc1ccccc1

Procedure:
A 250 mL round bottom flask was charged with 2-(S)-tert-butoxycarbonylamino-3-thiocarbamoyl-propionic acid benzyl ester (1.0 g, 2.96 mmol), dimethoxyethane (66 mL), and bromoacetate diethylacetal (2.4 mL, 15.5 mmol). The flask containing the resulting mixture was fit with a reflux condenser and the mixture refluxed for 3 h. The resulting mixture was then concentrated in vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF65-400 g column, gradient 100:0-90:10 CH2Cl2:MeOH) to yield 2-(S)-tert-butoxycarbonylamino-3-thiazol-2-yl-propionic acid benzyl ester. 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J=3.3 Hz, 1H), 7.29-7.44 (m, 5H), 7.20 (d, J=3.3 Hz, 1H), 5.15 (s, 2H), 5.75 (t, J=5.5 Hz, 1H), 73.15 (d, J=7.4 Hz, 1H), and 1.44 (s, 9H); MS (ES+) 363 (M+1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH3:34][C:35]1[O:39][N:38]=[C:37]([N:40]2[CH2:45][CH2:44][CH:43]([CH2:46][C:47](O)=[O:48])[CH2:42][CH2:41]2)[CH:36]=1>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH:25][C:47](=[O:48])[CH2:46][CH:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[C:35]([CH3:34])[O:39][N:38]=2)[CH2:45][CH2:44]1
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)no1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCC(CC(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 8 %

Procedure:
The desired compound was prepared according to the procedure of Example A169, step B using 6-chloro2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and [1-(5-methylisoxazol-3-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting materials in 8% yield. LCMS for C29H31ClN7O2 (M+H)+: m/z=544.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13]O>O1CCOCC1>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(O)c1

Procedure:
3-Hydroxyphenylacetic acid (5 g, 32.9 mmol) in MeOH was treated with 4N HCl in 1,4-dioxane (3 mL) at 80° C. for 3 hours. The solution was concentrated to dryness to give the desired product as a yellow oil (5 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH3:40])[CH:36]([NH:41][CH3:42])[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>O>[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH3:40])[CH:36]([N:41]([CH3:42])[C:2]2[C:3]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CNC1CN(Cc2ccccc2)CCC1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CN(Cc5ccccc5)CCC4C)ncnc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2 g, 6.37 mmol, 2.00 equiv.) and potassium carbonate (2.7 g, 19.4 mmol, 6.00 equiv.) were added to a solution of (1-benzyl-4-methyl-piperidin-3-yl)-methyl-amine (700 mg, 2.89 mmol, 1.00 equiv.) in water (30 mL). The solution was stirred at about 100° C. for about 16 hours, and then was cooled to ambient temperature. Following standard extractive workup with ethyl acetate (3×100 mL), the crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum (1:1)) to give the title product as a light yellow solid (1.5 g; yield=96%). 1H NMR (300 MHz, CDCl3) δ: 8.36 (s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.45 (d, J=4.2 Hz, 1H), 7.20-7.42 (m, 7H), 6.75 (d, J=4.2 Hz, 1H), 5.05-5.20 (m, 1H), 3.40-3.65 (m, 5H), 2.70-2.92 (m, 2H), 2.50-2.70 (m, 1H), 2.42 (s, 3H), 2.23-2.42 (m, 1H), 2.10-2.23 (m, 1H), 1.55-1.75 (m, 2H), 0.92 (d, J=6.9 Hz, 3H). LC-MS: m/z=490 (M+H)+.