Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Yield: 97.6 %

Procedure:
A solution of methyl 4-methyl-3-nitrobenzoate (4.46 g) in N,N-dimethylformamide (23 ml) was treated with N,N-dimethylformamide dimethyl acetal (8.18 g) and heated at 130° for 2 hours. The solvent was evaporated and the residue was triturated with ether to give methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (5.58 g, 98%) as a red powder; NMR (80 MHz, CDCl3): 2.98[s, 6H, N(CH3)2 ], 5.90(d, 1H, CHN), 7.14(d, 1H, CHCHN), 7.45(d, 1H, H5 -Ar), 7.90(dd, 1H, H6 -Ar), 8.47(d, 1H, H2 -Ar).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13](=O)[CH2:14]Br)[CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:4]3[CH:3]=[C:2]([OH:1])[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cc(O)cc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3cc(O)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-hydroxy-6-ethoxycarbonyl-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-hydroxy-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Sn:13](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17]>CCOC(C)=O>[CH2:22]([Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Temperature: -78 °C
Yield: 59.8 %

Procedure:
n-BuLi (200 mL, 0.5 mol) was added dropwise to 2-bromopyridine (79 g, 0.5 mol) under N2 with continuous stirring at −78° C. This solution was stirred at −78° C. for 1 h and (Bu)3SnCl (178.8 g, 0.55 mol) was added dropwise to the reaction solution. After addition, the reaction solution was stirred at −78° C. for 1 h and room temperature for 1 h. TLC (petroleum:EtOAc=10:1) indicated the reaction was complete. The reaction solution was quenched with sat. NH4Cl and extracted with EtOAc (350 mL×3). The combined extracts were washed with water, dried over Na2SO4, concentrated and purified by chromatography, eluted with (petroleum:EtOAc=10:1) to give title compound (110 g, 60%) as a yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:74]=[CH:73][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27][CH:28]([S:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]4[CH:64]=[CH:63][C:62]([C:65]5[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=5[C:71]#[N:72])=[CH:61][CH:60]=4)=[CH:47][CH:46]=3)[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[CH:33][CH:32]=3)=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)#[N:2].[CH3:75][I:76]>C(Cl)(Cl)Cl>[I-:76].[C:71]([C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=1[C:62]1[CH:63]=[CH:64][C:59]([O:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][O:51][C:48]2[CH:49]=[CH:50][C:45]([S:44][CH:28]([S:27][C:24]3[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]4[CH:11]=[CH:10][C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[C:1]#[N:2])=[CH:74][CH:73]=4)=[CH:26][CH:25]=3)[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N+:39]=4[CH3:75])=[CH:33][CH:32]=3)=[CH:46][CH:47]=2)=[CH:60][CH:61]=1)#[N:72]
Reactant: N#Cc1ccccc1-c1ccc(OCCCCCCOc2ccc(SC(COc3ccc(Sc4ccccn4)cc3)Sc3ccc(OCCCCCCOc4ccc(-c5ccccc5C#N)cc4)cc3)cc2)cc1
Reactant: CI
Solvent: ClC(Cl)Cl
Product: C[n+]1ccccc1Sc1ccc(OCC(Sc2ccc(OCCCCCCOc3ccc(-c4ccccc4C#N)cc3)cc2)Sc2ccc(OCCCCCCOc3ccc(-c4ccccc4C#N)cc3)cc2)cc1
Product: [I-]
Yield: 65.9 %

Procedure:
Into 20 mL of chloroform was dissolved 10 g of 2-(4-(2,2-bis(4-(6-(4-(cyanophenyl)phenoxy)hexyloxy)phenylthio)ethoxy)phenylthio)pyridine, and then 10 mL of methyl iodide was added thereto. The resultant solution was then heated under reflux. After the completion of the reaction, the solvent and an excess amount of methyl iodide were removed by distillation under reduced pressure. The residue was dissolved in chloroform, and purified by silica gel column chromatography (yielded amount 7.5 g, and yield 65.9%).
Reaction SMILES: O(C1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1.C(#N)CC#N.[C:22]([C:24]([C:40]#[N:41])=[C:25](O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)#[N:23].C[Si](C=[N+:47]=[N-:48])(C)C.O.NN>>[NH2:23][C:22]1[C:24]([C:40]#[N:41])=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[NH:48][N:47]=1
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: NN
Agent: O=C(O)c1ccc(Oc2ccccc2)cc1
Solvent: N#CCC#N
Solvent: O
Product: N#Cc1c(N)n[nH]c1-c1ccc(Oc2ccccc2)cc1

Procedure:
First, 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine may be prepared in accordance with procedures described in WO 2008/039218, for instance by converting 4-phenoxybenzoic acid to the corresponding acyl chloride (by using thionyl chloride), which latter product may be reacted with malononitrile to prepare 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene. The methoxy moiety is then methylated using trimethylsilyldiazomethane, and that methylated product is the treated with hydrazine hydrate to provide 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole, which is reacted with formamide to provide 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine, as illustrated in the following scheme:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][NH:8][C:9]2=[O:14])([O-])=O.Cl>CC(O)=O.C(O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][NH:8][C:9]2=[O:14]
Reactant: O=c1[nH]ccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cccc2c(=O)[nH]ccc12
Reaction time: 18 h

Procedure:
A mixture of 4.0 g (21 mmol) of 5-nitroisoquinolinone in 100 ml HOAc and 0.5 g 5% Pd-C was hydrogenated at room temperature for 18 hours (three atmospheres). The mixture was filtered and concentrated to give a solid. The solid was dissolved in ethanol (50 ml) and 10 ml of saturated ethanolic HCl was added. The solution was cooled and the resulting solid was collected. It was dissolved in water and the solution was neutralized with 100 ml concentrated NH4OH. The precipitate was collected, dissolved in 150 ml of hot methanol, treated with charcoal, filtered, and diluted with water. Upon cooling, 1.10 g (32%) of the desired product was collected; mp 258°-259°.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C(OCC)(=O)C>C1COCC1>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(C#N)cc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 490 mg, 12.2 mmol) in THF (10 mL) was added a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.46 g, 12.2 mmol) in THF (2 mL) at rt. The reaction mixture was stirred at rt for several minutes and then heated to reflux for 15 min. After cooling to rt 4-(bromomethyl)benzonitrile (2.00 g, 10.2 mmol) was added, and the reaction mixture was stirred at rt over night. Ethyl acetate was added and the mixture was washed with water. The organic layer was dried with anhydrous magnesium sulfate and filtered. The solvent was removed and the crude product was used as such for Step 2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].CCN(C(C)C)C(C)C.Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][N:24]([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2CC1
Yield: 110.3 %

Procedure:
7-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 17) (65 mg, 0.155 mmol), DIPEA (0.104 ml, 0.593 mmol) and ethyl 4-bromobutanoate (0.048 ml, 0.339 mmol) were stirred at 60° C. in DMF (10 ml) for 24 hours. The reaction mixture was partitioned between EtOAc (˜30 ml) and water (˜30 ml) and the aqueous layer extracted once more with EtOAc (˜40 ml). The combined organics were concentrated in vacuo to yield the crude title compound (100 mg, 0.171 mmol) as an orange solid. MS (ES): C27H3235ClN3O4 requires 497; found 498 [M+H]+.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[P:10]([OH:13])([OH:12])[OH:11].P(=O)(O)(O)O.[CH2:19]=O>O>[P:10]([CH2:19][N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])([OH:13])([OH:12])=[O:11]
Reactant: C=O
Reactant: OP(O)O
Reactant: O=C(O)CNCC(=O)O
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 140 °C
Yield: 71.7 %

Procedure:
In a three-necked round-bottom flask equipped with a mechanical stirrer, 33.28 g (0.25 mol) of iminodiacetic acid (IDA) were mixed with 20.5 g (0.25 mol, 1 eq.) of phosphorous acid, 122.5 g (1.25 mol, 5 eq.) of phosphoric acid and 13.6 g of water. The reaction mixture was heated to 140° C. 18.80 ml of 36.6 wt.-% aqueous solution of formaldehyde (1 eq.) were then added over 118 min. During the addition, the temperature of the reaction mixture decreased from 140° C. to 130° C. At the end of the formaldehyde addition the reaction mixture was kept at reflux for 30 min. The precipitate formed by cooling the reaction mixture was isolated by filtration and washed with fresh water. The dried precipitate was analysed by H and 31P NMR and identified as 91.4% pure N-(phosphonomethyl) iminodiacetic acid (PMIDA, 35.3 g, 71.7% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[CH2:8][OH:9].[C:26]1(OB(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([C:11]1[N:10]([CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2=[N:6][C:7]([CH2:8][OH:9])=[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:3]=[C:4]2[N:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: OB(O)Oc1ccccc1
Reactant: CCCCc1nc2cc(Br)c(CO)nc2n1CC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2n1CC(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
4.8 g(0.01197 mole) of the compound obtained in step 7, 3.75 g(0.03591 mole) of phenylboric acid, 0.2 g(0.0012 mole) of palladium acetate, 0.46 g(0.0024 mole) of triphenylphosphine and 8.9 ml(0.0838 mole) of triethylamine were dissolved in 20 ml of dimethyl formamide. The reaction solution was stirred for 3 hours at 120° C., diluted with 100 ml of ethyl acetate and washed with water(50 ml×3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified with column chromatography(5% MeOH in CH2 Cl2) to obtain 4.57 g of the title compound(yield 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][CH:12]=[CH2:13])[C:9]=1[OH:10])[CH2:5][OH:6].Br[CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([CH2:11][CH:12]=[CH2:13])[C:9]=1[O:10][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: C=CCc1cc(CO)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a magnetically stirred solution of 0.545 g (2.74 mmol) of the product of Step B in 10 mL acetone was added 0.628 g (2.74 mmol) of methyl α-bromophenylacetate, 0.757 g (5.48 mmol) of potassium carbonate and the reaction mixture was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.789 g (83%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.C(O)(=O)C.[Br:17]Br>O>[Br:17][C:3]1[C:4]2[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=2[S:12][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc2c(=O)[nH]c(=O)[nH]c2s1
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc2[nH]c(=O)[nH]c(=O)c2c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A brown glass round-bottom flask was charged with 6-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione (2.70 g, 14.8 mmol) and glacial acetic acid (30 ml). Bromine (2.70 ml) was added and the mixture stirred at ambient temperature for 4 hours. The resultant mixture was diluted with water (30 ml) and the solid was collected by filtration, washed thoroughly with water and then dried in vacuo to give 5-bromo-6-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione as a brown solid (2.43 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3F)=[N:14]/[OH:15])=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=4[O:15][N:14]=3)=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1/C(=N/O)c1cc(OC)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(OC)cc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of the oxime from Step 4 (1.4 g, 3.3 mmol) and cesium carbonate (2.1 g, 6.7 mmol) in DMF (20 mL) was stirred at 80° C. for 18 h. The reaction was diluted with ethyl acetate and washed with water. The crude product was purified by chromatography on silica gel to give the title product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[CH:45]=[CH:44][NH:43][C:40]3=[N:41][CH:42]=2)O1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[N:10]=[C:9]([C:11]4[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=4)[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[S:8][C:6]=3[N:7]=[C:2]([C:37]3[CH:38]=[C:39]4[CH:45]=[CH:44][NH:43][C:40]4=[N:41][CH:42]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Product: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(-c4cnc5[nH]ccc5c4)nc3s2)c1
Yield: 31.6 %

Procedure:
N-[3-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-benzyl]-methanesulfonamide (120 mg) was reacted with 80 mg of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine via General Procedure A. The product was purified by reverse phase HPLC to yield 45 mg of 115. MS (Q1) 522.2 (M)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][C@@H:19]([OH:26])[C@@:18]2([CH3:27])[C@:8]3([OH:28])[CH2:9][CH2:10][C@@H:11]2[C:12]2(OCCO2)[CH3:13])[CH2:3]1>C(O)(=O)C>[OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][C@@H:19]([OH:26])[C@@:18]2([CH3:27])[C@:8]3([OH:28])[CH2:9][CH2:10][C@@H:11]2[CH2:12][CH3:13])[CH2:3]1
Reactant: CC1([C@H]2CC[C@]3(O)[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4C[C@@H](O)[C@]23C)OCCO1
Solvent: CC(=O)O
Product: CC[C@H]1CC[C@]2(O)[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3C[C@@H](O)[C@]12C
Yield: 93.4 %

Procedure:
The ethylenedioxypregnene (25) (250 mg, 0.64 mmol) is dissolved in acetic acid (13.4 ml) and water which after freeze drying affords the trihydroxy steroid (15) (200 mg, 89%), m.p.: 228°–235° C. (lit. 225°–235° C.), M+348, [αD]20 +35° (lit [αD]20+29°).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:15]=2)[CH:10]=[C:9]1[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:27]=[N:26][C:25]=1[O:36][CH3:37])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[CH3:37][O:36][C:25]1[N:26]=[N:27][C:28]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)=[CH:29][C:24]=1[C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[C:14]([CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH:15]=2
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CN3CCCCC3)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CN3CCCCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
1.30 g 6-(Piperidin-1-ylmethyl)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester (see example 37) are dissolved in 2 mL dichloromethane. 0.97 mL trifluoroacetic acid and 4 drops of water are added. The reaction mixture is stirred overnight at rt. Concentration in vacuo affords 1.05 g (100%) crude product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:36][O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=1>C1COCC1.CO>[CH3:36][O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][N:8]2[C:9]3[C:5](=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=3)[C:6]([CH3:18])=[C:7]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:41][CH:40]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cn2c(-c3cccnc3)c(C)c3cc(Cl)ccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 558 mg, 2.0 mmol) in THF (20 mL) is added 0.5 M KHMDS in toluene (8.8 mL, 4.4 mmol) and the mixture is stirred at room temperature for 30 min, whereupon 4-bromomethyl-benzoic acid methyl ester (916 mg, 4.0 mmol). The reaction mixture is stirred for 3 h. Methanol is added to quench the reaction and the solvents are removed in vacuo. The residue is purified by flash chromatography with 1-3% methanol in dichloromethane to give 4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid methyl ester. MS (ESI) m/z 391.3 and 393.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[N:9]=[C:10]([N:25]3[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]3)[S:11][C:12]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.[CH3:36][NH:37][CH2:38][CH2:39][C:40]#[N:41].C(O)(=O)C.C([BH3-])#N>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[N:9]=[C:10]([N:25]3[CH2:26][CH2:27][CH:28]([N:37]([CH2:38][CH2:39][C:40]#[N:41])[CH3:36])[CH2:29][CH2:30]3)[S:11][C:12]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1
Reactant: O=C1CCN(c2nc(-c3cc(Cl)ccc3OC(F)F)c(NC(=O)c3cnn4cccnc34)s2)CC1
Reactant: CNCCC#N
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCC#N)C1CCN(c2nc(-c3cc(Cl)ccc3OC(F)F)c(NC(=O)c3cnn4cccnc34)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-oxo-piperidin-1-yl)-thiazol-5-yl]-amide (90 mg, 0.17 mmol) was dissolved in DCM (2 ml) and N-methyl-β-alaninenitrile (20 μl, 0.21 mmol), acetic acid (200 μl) and macroporous polymer supported cyanoborohydride (166 mg, 0.36 mmol) were successively added and stirred at room temperature for 16 hours. The mixture was diluted with MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by MDAP (Method 1). Appropriate fractions were combined and evaporated to afford a yellow glass. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a yellow solid (46 mg, 46%). LCMS (Method 5) [M+H]+=587.2, RT=3.19 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.23 (s, 1H), 9.36 (dd, 1H, J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.64 (dd, 1H, J=1.6, 4.3 Hz), 7.67 (d, 1H, J=2.6 Hz), 7.59 (dd, 1H, J=2.7, 8.9 Hz), 7.41 (d, 1H, J=8.6 Hz), 7.31 (dd, 1H, J=4.3, 7.1 Hz), 7.18 (t, 1H, J=73.9 Hz), 3.94 (d, 2H, J=12.8 Hz), 3.04-2.96 (m, 2H), 2.72-2.60 (m, 5H), 2.24 (s, 3H), 1.79 (d, 2H, J=10.9 Hz), 1.59-1.47 (m, 2H).