Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccccc1N
Reaction time: 18 h

Procedure:
A solution of ethyl 2-nitrophenylacetate (13.6 g, 0.065 mole) in ethanol (150 ml) was hydrogenated over 10% Pd/C catalyst (1 g) at room temperature and pressure for 18 hours. The reaction mixture was filtered through keiselguhr and concentrated in vacuo to afford the title compound as a clear oil, which solidified on standing (10.8 g, 93%).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27])=[O:20]>>[C:13]([O:12][C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[C:26]#[N:27])=[O:20])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: CC(C)(C)OC(=O)C12CCC(N)(CC1)CC2
Product: CC(C)(C)OC(=O)C12CCC(NCC(=O)N3CCC[C@H]3C#N)(CC1)CC2
Yield: 65.1 %

Procedure:
In a similar manner to Example 2, t-butyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (100 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (90.0 mg) were used to obtain (2S)-1-[[N-(4-t-butoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (97.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](Cl)=[N:7][OH:8])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1.N>>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]2[O:8][N:7]=[C:6]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[CH:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: ON=C(Cl)c1ccc(Cl)nc1
Agent: N
Product: Clc1cccc(-c2cc(-c3ccc(Cl)nc3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 95B (79 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, CDCl3) δ6.88 (s, 1H), 7.43-7.52 (m, 3H), 7.69-7.78 (m, 1H), 7.81-7.89 (m, 1H), 8.18 (dd, J=8.3, 2.4 Hz, 1H), 8.84 (d, J=2.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)(=O)=O.[CH2:29]1[CH:33]2[CH2:34][NH:35][CH2:36][CH:32]2[CH2:31][N:30]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:8][CH2:7][CH2:6][N:35]2[CH2:34][CH:33]3[CH2:29][N:30]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31][CH:32]3[CH2:36]2)=[CH:26][CH:25]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: COc1ccc(OC(CCCOS(C)(=O)=O)c2ccc(C#N)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(OC(CCCN2CC3CN(C(=O)OC(C)(C)C)CC3C2)c2ccc(C#N)cc2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate (1.12 g, 2.8 mmol; see step (c) above), tert-butyl hexahydropyrrolo[3,4-c]-pyrrole-2(1H)-carboxylate (0.59 g, 2.8 mmol; see Preparation A above) and Cs2CO3 were mixed in CH3CN (30 mL) and stirred at rt for 3 days. The mixture was then filtered and evaporated. Purification on silica (ethyl acetate:MeOH (9:1) eluant) gave 0.9 g (60%) of the sub-title compound.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH:25]=[CH:26][CH:27]=O>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH:25]=[CH:26][CH:27]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CC=Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1c(F)cccc1F
Reaction time: 3 h

Procedure:
Ethyl (diethoxy-phosphoryl)-acetate (3.72 ml, 18.7 mmol) in solution in THF (114 ml) is treated with sodium hydride (60% in oil) (819 mg, 20.4 mmol) at room temperature for 5 minutes. 3-(2,6-Difluoro-phenyl)-propenal (2.87 g, 17.0 mmol) in solution in THF (29 ml) is then added dropwise. After 3 hours of agitation at room temperature, the mixture is evaporated to dryness, taken up in ethyl acetate and washed with water. The organic phase is dried on Na2SO4, filtered and evaporated to dryness. The yellow solid obtained is used directly in the following reaction.
Reaction SMILES: I[CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].[N-:19]=[N+:20]=[N-:21].[Na+].CN(C=O)C>>[N:19]([CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18])=[N+:20]=[N-:21]
Reactant: CC1(C)CC(I)C(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(N=[N+]=[N-])C(=O)Nc2cc([N+](=O)[O-])ccc21

Procedure:
3-Iodo-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (5.367 g, 0.015 mol), Sodium azide (6.49 g, 0.1 mol), and DMF (100 mL, 2 mol) were stirred at rt for 2 h. The reaction mixture was diluted with H20 and the resulting beige ppt was filtered.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH2:27][CH:28]=O>C(O)C>[ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:8]1[CH:28]([CH2:27][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:25]=[CH:26][C:17]=3[O:16][CH3:15])[NH:12][CH2:11][CH2:10][C:9]2=1
Reactant: COc1ccc2ccccc2c1CC=O
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Agent: Cl
Solvent: CCO
Product: COc1ccc2ccccc2c1CC1NCCc2c1[nH]c1ccc(C)cc21
Temperature: 25 °C

Procedure:
To a stirred solution of 5-methyltryptamine hydrochloride (947 mg, 4.49 mmol) in 20 mL of ethyl alcohol was added (2-methoxy-1-naphthyl)-acetaldehyde (1.0 g, 4.99 mmol). The solution was heated to reflux under nitrogen atmosphere for 40 hours. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. Recrystallization from ethyl alcohol/2-butanone afforded product as a pale solid (705 mg). (mp. 245.3° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CNc1cc(C)ccn1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(N(C)C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), methyl-(4-methyl-pyridin-2-yl)-amine (88 mg, 0.72 mmol), BOP (137 mg, 0.31 mmol) and DIEA (265 L, 1.44 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-(4-methyl-pyridin-2-yl)-amide: MS m/z: 519.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]1=[O:16])[O:6][CH2:7][CH3:8])[CH3:2].N1C(C)=CC(C)=CC=1C.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:6][CH2:7][CH3:8])[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:34]([CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:36])=[O:35])[C:10]1=[O:16])[CH3:2]
Reactant: CCOC(=O)C(OCC)n1cccc(N)c1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)C(OCC)n1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a stirred, cooled (0° C.) solution (RS)-(3-amino-2-oxo-2H-pyridin-1-yl)-ethoxy-acetic acid ethyl ester (428 mg) and 2,4,6-collidine (0.47 ml) in THF (3 ml) under an argon atmosphere was added dropwise a solution of alpha-toluenesulphonylchloride (340 mg) in THF (2 ml) over 10 min. When addition was complete, stirring at 0° C. was continued for 2 h. The mixture was diluted with EtOAc, washed with 1.0 N HCl and brine, dried (MgSO4), filtered and concentrated to give (RS)-ethoxy-(2-oxo-3-phenylmethanesulfonylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (592 mg) as light brown solid. MS 393.0 ([M−H]−)
Reaction SMILES: [CH2:1]([SiH](CC)CC)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:20][O:21][C:22]1[C:37]([O:38][CH3:39])=[C:36]([O:40][CH3:41])[C:35]([O:42][CH3:43])=[C:34]([CH3:44])[C:23]=1[CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C:23]2[C:34]([CH3:44])=[C:35]([O:42][CH3:43])[C:36]([O:40][CH3:41])=[C:37]([O:38][CH3:39])[C:22]=2[O:21][CH3:20])=[CH:33][CH:32]=1
Reactant: CC[SiH](CC)CC
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)cc2)c(OC)c(OC)c1OC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
To a solution of triethylsilane (88 mg, 0.76 mmol) and TMSOTf (0.004 ml) in methylene chloride (2 ml) was added dropwise a solution of the compound (237 mg, 0.63 mmol) obtained in Step 2 in methylene chloride (2 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated saline, dried, and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:6) to yield the title compound (160 mg, 0.45 mmol, yield 71%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.26) (0.65 g, 1.65 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.468 g, 1.82 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 12%) and additional off-white solid (0.57 g, 66%). MS (ISP) 526.2 [(M+H)+]; mp 183° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17](Br)[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2].[CH3:27][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17]([CH3:27])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c3ccccc3n(-c3ccccc3)c2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(C)c2c3ccccc3n(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to that of Example 103(b) from 1-bromo-4-hydroxy-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester, tetramethyl tin, and bis(triphenylphosphine)-palladium(II) dichloride (Pd(PPh3)2Cl2). The title compound, ESI MS (m/z): 347 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:29][C:30]([CH3:36])=[C:31]([C:33]([OH:35])=O)[N:32]=1)([CH3:27])[CH3:26].[O:37]1[C:42]2([CH2:47][CH2:46][N:45]([CH2:48][C:49]3[C:50]([F:58])=[C:51]([CH2:55][CH2:56][OH:57])[CH:52]=[CH:53][CH:54]=3)[CH2:44][CH2:43]2)[CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN(C=O)C>[F:58][C:50]1[C:51]([CH2:55][CH2:56][OH:57])=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][N:45]1[CH2:46][CH2:47][C:42]2([O:37][CH2:38][CH2:39][N:40]([C:33]([C:31]3[N:32]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:29][C:30]=3[CH3:36])=[O:35])[CH2:41]2)[CH2:43][CH2:44]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: Cc1sc(C(C)C)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1sc(C(C)C)nc1C(=O)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.175 g) was added in one portion to a stirred solution at 0° C. of 2-isopropyl-5-methylthiazole-4-carboxylic acid (example 69, step b) (0.066 mg) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.109 g) and triethylamine (0.148 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.155 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[N:7][N:6]=[CH:5]2.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:42]1[CH:43]=[C:44]([CH:51]=[CH:52][C:53]=1[CH3:54])[C:45]([NH:47][CH:48]1[CH2:50][CH2:49]1)=[O:46].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.CCOC(C)=O.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].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.C(O)C>[CH:48]1([NH:47][C:45](=[O:46])[C:44]2[CH:51]=[CH:52][C:53]([CH3:54])=[C:42]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[N:7][N:6]=[CH:5]4)[CH:43]=2)[CH2:49][CH2:50]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Br
Reactant: CN(C)CCNc1nncc2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(NCCN(C)C)nncc2c1
Temperature: 160 °C

Procedure:
6-Bromo-N-(2-(dimethylamino)ethyl)phthalazin-1-amine (115 mg, 390 μmol), potassium acetate (53 mg, 550 μmol), bis(pinacolato)diboron (139 mg, 550 μmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (29 mg, 40 μmol) were suspended in dioxane (4 mL) and placed in the microwave for I 0 min at 160° C. To the reaction was added a mixture of 3-bromo-N-cyclopropyl-4-methylbenzamide (99 mg, 390 μmol), sodium carbonate-2 M in water (0.29 mL, 0.58 mmol), tetrakis(triphenylphosphine)palladium (45 mg, 40 μmol), and ethyl alcohol (5 mL). The reaction was heated in the microwave for 10 min at 160° C. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3× with 20 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated via rotovap to give a crude product. The crude product was purified by chromatography to obtain the title compound. Found MS (ES+): 390(M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([F:13])=[C:4]([C:7]([F:12])=[C:8]([F:11])[C:9]=1[F:10])[C:5]#N.[OH-].[Na+]>>[F:12][C:7]1[C:8]([F:11])=[C:9]([F:10])[CH:2]=[C:3]([F:13])[C:4]=1[CH3:5]
Reactant: N#Cc1c(F)c(F)c(F)c(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)cc(F)c(F)c1F
Yield: 77.3 %

Procedure:
3-Chloro-tetrafluorobenzonitrile was reacted at 240° C. The reaction products were collected in 300 ml of water and, after reaction was complete, the mixture was made alkaline with 40% strength by weight aqueous sodium hydroxide solution. The organic material was extracted with methyl tert.-butyl ether, analysed and then worked up by distillation. 2,3,4,6-Tetrafluoro-toluene of boiling point 108° C. was isolated in a yield of 77.3%.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][O:22]C(=O)CC)[C:15](=[CH:16][CH2:17][CH2:18][C@@H:19]1[CH3:30])[CH2:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3].C(=O)(O)[O-].[Na+]>CO>[C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][OH:22])[C:15](=[CH:16][CH2:17][CH2:18][C@@H:19]1[CH3:30])[CH2:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OC[C@@]12C(=CCC[C@@H]1C)CC[C@H]1[C@@H]3CC[C@H](OC(=O)CC)[C@@]3(C)CC[C@@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CCC[C@H](C)[C@]4(CO)[C@H]3CC[C@]12C

Procedure:
1α-Methyl-4-androstene-17β,19-diol dipropionate is dissolved in a 10% aqueous methanol solution and one equivalent of sodium bicarbonate is added. The solution is stirred and heated at its reflux temperature for one hour and poured onto ice water with vigorous stirring. The precipitate is removed by filtration, air dried and crystallized from hexane to yield 1α-methyl-4-androstene-17β,19-diol 17-propionate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:14](O)=[N:13][CH:12]=[N:11][C:10]=2[S:9][CH:8]=1.P(Cl)(Cl)([Cl:19])=O>O1CCOCC1>[Cl:19][C:14]1[C:15]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][S:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Oc1ncnc2scc(-c3ccccn3)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Clc1ncnc2scc(-c3ccccn3)c12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 100-mL round-bottom flask was charged with 5-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-ol (2 g, 8.72 mmol, 1.00 equiv) and dioxane (30 mL). This was followed by the addition of phosphoroyl trichloride (4.0 g, 26.09 mmol, 2.99 equiv), in portions at room temperature. The resulting solution was stirred overnight at 110° C. The resulting mixture was concentrated under vacuum. The residue was then quenched by the addition of 50 mL of water/ice. The pH value of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate. The solids were collected by filtration and dried under vacuum. This resulted in 1.0 g (46%) of 2-[4-chlorothieno[2,3-d]pyrimidin-5-yl]pyridine as a gray solid. MS: m/z 248 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O>ClCCl>[CH2:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:22]2=[O:24])[CH2:15][CH2:14]1)=[O:17])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2N)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cccc(C)c32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
4-[(2-Amino-6-methylphenyl)amino]-1-ethoxycarbonylpiperidine (75.2 mg) was dissolved in dichloromethane (1.5 ml), added with triphosgene (80.5 mg) and triethylamine (76 μl) and stirred at room temperature for 2 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:1) to obtain 59.1 mg of the title compound. Yield: 72%.
Reaction SMILES: N[C@H](CC1C=CC(Cl)=CC=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([Br:17])=[CH:15][N:14]=[C:13]3[NH:18][CH:19]=[CH:20][C:12]=23)[CH2:7][CH2:6]1)=[O:4].[C:29]([O:33][C:34]([N:36]([CH:49]([CH3:51])[CH3:50])[CH2:37][C@H:38]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)C(O)=O)=[O:35])([CH3:32])([CH3:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[Br:17][C:16]1[C:11]([N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:38]([C:42]3[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=3)[CH2:37][N:36]([CH:49]([CH3:51])[CH3:50])[C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:32])[CH3:30])[CH2:10][CH2:9]2)=[C:12]2[CH:20]=[CH:19][NH:18][C:13]2=[N:14][CH:15]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Yield: 60.4 %

Procedure:
5-Bromo-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.100 g, 0.282 mmol, see Example 1), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.145 g, 0.424 mmol, see Example H), HOBT-H2O (0.0606 g, 0.395 mmol), EDCI (0.0704 g, 0.367 mmol), and triethylamine (0.0394 mL, 0.282 mmol) were stirred in DCM (5 mL) at room temperature for 5 hours. The reaction was then quenched with saturated Na2CO3 and extracted into DCM. The organics were dried, filtered, and concentrated to give the crude product. Purification (500:6 DCM:MeOH) gave (S)-tert-butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.103 g, 60.2% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.C(N(CC1C=CC=CC=1)[C:17](=[O:22])[CH2:18][CH2:19][O:20][CH3:21])C>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([C:17](=[O:22])[CH2:18][CH2:19][O:20][CH3:21])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCN(Cc1ccccc1)C(=O)CCOC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCC(=O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
To a solution of n-Butyllithium (1.6M in hexanes, 4.06 mL, 6.50 mmol) in anhydrous THF (4.0 mL) under nitrogen at −78° C. was added a solution of 2,6-dibromopyridine (1.54 g, 6.50 mmol) in anhydrous THF (9.5 mL) drop-wise over 45 min. The resulting dark green solution was stirred at −78° C. for 15 min and then treated with N-ethyl-3-(methyloxy)-N-(phenylmethyl)propanamide (2.16 g, 9.76 mmol), washing in with anhydrous THF (3.0 mL). The resulting green solution was stirred at −78° C. for 15 min and was then treated with a solution of AcOH (0.40 mL) in MeOH (6.60 mL) to give a pale brown solution. This mixture was removed from the cooling bath and allowed to warm to room temperature, then stirred for 2 h. The mixture was then treated with saturated aqueous. NH4Cl (40 mL) and the products extracted with EtOAc (2×50 mL). The combined organic layer was then washed with brine (60 mL), dried (MgSO4) and the reduced in vacuo to give an orange oil. Purification by Biotage (silica, 90 g cartridge) eluting with cyclohexane:EtOAc (10:1) afforded the title compound as a white solid (547 mg).