Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[O:27][C:28](=[O:31])[CH2:29]I)[CH3:2].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].O>C(Cl)Cl>[CH2:32]([N:34]([CH2:29][C:28]([O:27][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)=[O:31])[CH2:35][CH3:36])[CH3:33]
Reactant: CCNCC
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CI
Solvent: ClCCl
Solvent: O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CN(CC)CC
Temperature: 25 °C

Procedure:
2β-Ethoxy-3α-iodoacetoxy-5α-pregnane-11,20-dione (460 mg) was dissolved in methylene chloride (25 ml) and diethylamine (1 ml) added to the solution. The mixture was stirred at room temperature for one-half hour. The mixture was poured into water and the organic layer washed with water (100 ml.), dried over anhydrous sodium sulphate and evaporated to a red oil (410 mg.) which was purified by preparative T.L.C. using ethyl acetate/petrol (2/1) run twice. The main band (RF 0.4) gave title compound (230 mg) as a pale yellow oil [α]D + 100° (c = 0.9).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([N:29]([CH3:30])[CH3:28])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)N(C)C)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.51 g, 1.32 mmol) in CH3CN, was added solid dimethylamine hydrochloride. The reaction was stirred at room temperature until complete by TLC (1 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of EtOAc and hexanes (1:1), providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3,3-dimethylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.51 g, 91% yield). 1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3H), 2.02 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 3.17 (s, 6H), 3.79-3.82 (m, 1H), 4.06-4.13 (m, 1H), 4.22 (dd, 1H, J=4.7, 12.5 Hz), 5.16-5.24 (m, 2H), 5.31 (dd, 1H, J=9.4 Hz), 5.72 (d, 1H, J=9.2 Hz), 5.77 (d, 1H, J=8.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)[CH2:6][OH:7]
Reactant: OB(O)c1cccs1
Reactant: OCCc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: OCC(c1ccccc1)c1cccs1

Procedure:
3-Bromophenethyl alcohol (4 ml, 29.8 mmol) was dissolved in 1,2-dimethoxyethane (225 mL) and mixed with tetrakistriphenylphosphine palladium[0] (2.6 g, 2.25 mmol) at room temperature. The reaction mixture was then added to a solution of 2-thienyl-boronic acid (12.6 g, 99 mmol) and 1 N NaHCO3 (90 mL). The reaction mixture was heated to reflux under nitrogen atmosphere for 48 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was dried with MgSO4, filtered through a plug of silica and the solvent was evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (30% EtOAc/hexane) to yield the title compounds as an oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:14][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:2]=1[Br:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(Br)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Add 1-bromo-6-methoxy-naphthalen-2-ol (66.7 g, 264 mmol), potassium carbonate (K2CO3, 40.0 g, 290 mmol) and benzyl bromide (49.6 g, 290 mmol) to DMF (800 mL). Stir the mixture at ambient temperature for 1 hour. Add water (400 mL) to precipitate the product. Collect the precipitate and wash the filter cake with heptane (3×125 mL) then dry to provide 83.7 g of 2-benzyloxy-1-bromo-6-methoxy-naphthalene (86.2%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCc2ccc(Br)cc2)cc1
Yield: 73.1 %

Procedure:
Methyl 4-hydroxybenzoate (1.09 g, 7.14 mmol), 2-(4-bromophenyl)ethanol (1.44 g, 7.14 mmol), and triphenylphosphine (2.06 g, 7.86 mmol) were dissolved in THF (44 mL), and then diethyl azodicarboxylate (3.57 mL, 40% toluene solution, 7.86 mmol) was added thereto while stirring under ice-cooling. The mixture was further stirred at room temperature for 2 days, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 19:1 to 9:1, v/v) to give 1.75 g of the title compound (white powder, yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O.[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC1C(CC)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([NH:28][NH:27][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15]
Reactant: NNC(=O)c1ccccc1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)O
Agent: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)NNC(=O)c1ccccc1
Yield: 49.7 %

Procedure:
(2R,3S)-2-(2,3-dichloro-4-cyanophenylamino)-3-hydroxybutanoic acid (1.0 g, 3.46 mmol) and benzohydrazide (471 mg, 3.46 mmol) were reacted using the techniques described for the preparation of intermediate 11c to furnish the title compound (700 mg, 50%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.7 (br s, 2H), 7.91 (d, J=8 Hz, 2H), 7.41-7.62 (m, 4H), 6.82 (d, J=8 Hz, 1H), 6.18 (d, J=7 Hz, 1H), 4.90 (br s, 1H), 4.38-4.41 (m, 1H), 4.19-4.21 (m, 1H) and 1.32 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:11])=O)=[C:6]([CH:8]=1)[NH2:7].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:11])=[C:6]([NH:7][S:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)(=[O:19])=[O:18])[CH:8]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CS(=O)c1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1cccs1

Procedure:
Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylsulfinyl)aniline and thiophene-2-sulfonyl chloride.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:53][C:54]1[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][CH:55]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:62][CH:63]=3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C(=O)OC)cc2)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.05 M) was added methyl 4-(bromomethyl)benzoate (1.6 eq.) and cesium carbonate (1.3 eq.). The reaction was heated to 80° C. and stirred for 12 h. After cooling to rt, the reaction was diluted with ether and quenched with water. The aqueous layer was extracted with ether. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in Hex→100% EtOAc) to afford the title compound as a foam.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc3ccccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(OCC3CCNC3)cccc2c1
Yield: 72.2 %

Procedure:
A solution of 0.42 g (1.28 mmol) of 1,1-dimethylethyl 3-[(1-naphthalenyloxy)methyl]-1-pyrrolidinecarboxylate, prepared in Step 12.1, in 10 ml of 1,4-dioxane and 6 ml of a 2N solution of aqueous hydrochloric acid is stirred for 6 hours. It is evaporated to dryness and then coevaporation is carried out twice with toluene. The solid residue is washed with diethyl ether. The solid is taken up in dichloromethane and concentrated ammonia solution is added until a basic pH is obtained. The system is filtered on a Whatman PTFE cartridge and the organic phase is concentrated, to give 0.21 g of oily product, which is used as it is in the following step.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+].Cl>CN1CCCC1=O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(-n2cncn2)cc1
Temperature: 190 °C

Procedure:
To a solution of ethyl 4-fluoro-benzoate (1.68 g) in N-methyl-pyrrolidinone (10 mL) is added 1,2,4-triazole (2.5 g) and K2CO3 (1.5 g) and the mixture is heated at 190° C. in a microwave oven for 30 min. After cooling to room temperature, the mixture is acidified with 2 M aqueous HCl and the precipitate is filtered off, washed with a small amount of water and methanol/dichloromethane and dried by suction to give the acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:24])=[C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:16]=3)[C:11](=[O:25])[C:10]([C:26]([O:28]CC)=[O:27])=[CH:9]2)=[N:6][CH:7]=1.[ClH:31]>O>[ClH:31].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:24])=[C:15]([N:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)[N:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cn2)c2nc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cn2)c2nc(N3CCNCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.5 g of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is added to 10 ml of water and 10 ml of conc. hydrochloric acid. The mixture is refluxed for 24 hours, cooled to room temperature and concentrated under a reduced pressure. The concentrate is added with 20 ml of ethanol and stirred at room temperature for 2 hours, filtered and dried. The product is recrystallized in a mixed solvent of water and methanol to obtain 0.39 g of the desired compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].O>ClCCl.C(OCC)(=O)C>[N:2]1([C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:19])[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[CH2:4][CH2:3]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
17.0 g (99.2 mmol) of thiomorpholine 1,1-dioxide hydrochloride were initially charged in 100 ml of dichloromethane and, while cooling with an ice bath, admixed with 20.7 ml (15.1 g, 148.8 mmol) of triethylamine. 10.0 g (49.6 mmol) of 4-nitrophenyl chloroformate were added in portions. The reaction mixture was stirred at RT for 30 minutes, admixed with water and ethyl acetate and then filtered. The residue was dried under high vacuum. Yield: 12.4 g (83% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Mg].CC.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15].[NH4+].[Cl-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: CC
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
Dropwise over 30 minutes, 26.4 g of p-bromophenyl acetylene in solution in 100 ml of tetrahydrofuran were added to 215 ml of the magnesium compound solution prepared above and the reaction was lively and immediately was accompanied by an evolution of ethane and a rise in temperature. The temperature was brought back to 15°-20° C. and stirring was continued for 10 minutes. Over 5 minutes, 20 ml of chlorotrimethylsilane was added dropwise and after allowing the temperature to return to the ambient and stirring for 30 minutes, the reaction medium was diluted by the addition of 200 ml of a saturated aqueous solution of NH4Cl, followed by decanting and extracting with tetrahydrofuran. The extracts were washed with salted water, dried and concentrated to dryness by distilling under reduced pressure. The oily residue was taken up in 150 ml of methanol and crystallization was initated. The crystals were separated, washed and dried to obtain 18.67 g of p-bromophenylethynyl trimethylsilane melting at about 65° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(=O)=O.[Br-:14].[Li+]>CC(C)=O>[Br:14][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCCC1CCOCC1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: BrCCC1CCOCC1
Yield: 73.4 %

Procedure:
To a stirring solution of 2-(4-oxanyl)ethyl methanesulfonate (11.9 g, 56.9 mmol) in dry acetone (300 mL) was added lithium bromide (29.7 g, 56.9 mmol). The reaction was refluxed under an N2 atmosphere for 5 h. The acetone was removed by rotary evaporation, water (150 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to yield a light brown oil. The crude compound was then distilled (65° C., 0.2 mm) to yield 8.06 g of a colorless oil (73.3% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[CH3:22][N:23]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH3:24].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:19]2[CH2:20][CH2:21][CH:16]([O:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][N:10]=4)[N:4]=3)[CH2:17][CH2:18]2)=[O:31])=[CH:33][CH:34]=1)[CH3:22]
Reactant: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Reactant: CN(C)Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(C(=O)N2CCC(Oc3nc(-c4ccncn4)cc(=O)n3C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a mixture of 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (290 mg, 1.0 mmol), 4-dimethylaminomethyl benzoic acid (180 mg, 1.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (380 mg, 2.0 mmol) and 1-hydroxybenzotriazole monohydrate (310 mg, 2.0 mmol) in N,N-dimethylformamide (10 ml) was added N,N-diisopropylethylamine (130 mg, 1.0 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was partitioned between water and dichloromethane. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=15/85) to afford 2-[1-(4-dimethylaminomethyl-benzoyl)piperidin-4-yloxy]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (66 mg, 0.15 mmol, 15%).
Reaction SMILES: O[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[Cl:29][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1cc(-c2ccccc2)c2cc(C(O)c3cccc(F)c3)ccc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=c1cc(-c2ccccc2)c2cc(C(Cl)c3cccc(F)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
A mixture of (±)-6-[hydroxy(3-fluorophenyl)methyl]-4-phenyl-2(1H)-quinolinone (11 g) of thionyl chloride (11 ml) and DCM (120 ml) was stirred at room temperature for 12 hours. The solvent was evaporated till dryness and used without further purification, yielding 11.6 g (±)-6-[chloro(3-fluorophenyl)methyl]-4-phenyl-2(1H)-quinolinone (100%) (interm. 3).
Reaction SMILES: [C:1]([NH:4][C:5](=S)[NH:6][C:7]1[N:12]=[C:11]2[N:13]([CH2:25][CH3:26])[C:14]([C:16]([N:18]([CH:22]3[CH2:24][CH2:23]3)[CH:19]3[CH2:21][CH2:20]3)=[O:17])=[CH:15][C:10]2=[C:9]2[N:27]([CH3:30])[CH:28]=[N:29][C:8]=12)(=O)[CH3:2].[CH3:32][NH:33][NH2:34]>C(O)(=O)C>[CH:19]1([N:18]([CH:22]2[CH2:23][CH2:24]2)[C:16]([C:14]2[N:13]([CH2:25][CH3:26])[C:11]3=[N:12][C:7]([NH:6][C:5]4[N:4]=[C:1]([CH3:2])[N:33]([CH3:32])[N:34]=4)=[C:8]4[N:29]=[CH:28][N:27]([CH3:30])[C:9]4=[C:10]3[CH:15]=2)=[O:17])[CH2:20][CH2:21]1
Reactant: CNN
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)NC(C)=O)nc21
Solvent: CC(=O)O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)n(C)n3)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
A mixture of 4-(3-acetylthioureido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 125A, 17 mg, 0.039 mmol) and methylhydrazine (2.486 μL, 0.046 mmol) in acetic acid (0.5 mL) was heated at 80° C. for 4 h, LC/MS showed starting material still remaining. Additional methylhydrazine (2.486 μL, 0.046 mmol) was added and heating continued for another 2 h, reaction complete. Solvent was evaporated and the crude was purified by preparative HPLC to furnish N,N-dicyclopropyl-4-(1,5-dimethyl-1H-1,2,4-triazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (5.2 mg, 30.7% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:16][CH2:17][CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: BrCCCn1ccc2ccccc21
Reactant: CCc1nc(N)nc(N)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCc1nc(N)nc(N)c1OCCCn1ccc2ccccc21
Reaction time: 1 h
Yield: 48 %

Procedure:
2,4-diamino-6-ethyl-5-hydroxypyrimidine (0.4625 g, 3 mmol) was added to a stirred solution of lithium hydroxide monohydrate (0.3147 g, 7.5 mmol) in DMF (2 mL) and the reaction mixture was stirred for 1 hour. A solution of 1-(3-bromopropyl)indole (0.7144 g, 3 mmol) in DMF (1 mL) was added and the reaction mixture was left stirring at 25° C. overnight. The reaction was diluted with dichloromethane and extracted with water. The dichloromethane layer was evaporated and the residue was recrystallized from aqueous methanol. The product was obtained as a slightly yellow solid (0.4484 g, 48%). 1H NMR (DMSO-d6): 1.02 (3H, t, J=7.5 Hz), 2.20 (2H, m), 2.32 (2H, q, J=7.5 Hz), 3.60 (2H, t, J=6.3 Hz), 4.34 (2H, t, J=7.2 Hz), 5.56 (2H, s), 6.07 (2H, s), 6.43 (1H, d, J=3.1 Hz), 7.01 (1H, m), 7.13 (1H, m), 7.40 (1H, d, J=3.1 Hz), 7.50 (1H, d, J=8.3 Hz), 7.54 (1H, d, J=7.8 Hz).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10](=[CH:15][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Cl)cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Methane sulphonyl chloride (7.0 g) was added to a stirred, cooled mixture of methyl 4-chlorosalicylate (10.0 g) and triethylamine (8.0 g) in dichloromethane while maintaining the temperature at 0° C. The mixture was then stirred at room temperature for half and hour and left to stand overnight. The mixture was washed with hydrochloric acid (2M) saturated aqueous sodium bicarbonate solution, water, dried (Na2 SO4) and filtered. The filtrate was evaporated to dryness to give methyl 4-chloro-2-(methylsulphonyloxy)benzoate (11.7 g) as an orange solid m.p. 82.5°-84.5° C.