Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][C:17]3[N:18]([C:20]([C:23]4([C:26]5[CH:27]=[C:28]6[C:33](=[CH:34][CH:35]=5)[N:32]=[CH:31][CH:30]=[CH:29]6)[CH2:25][CH2:24]4)=[CH:21][N:22]=3)[CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][C:17]3[N:18]([C:20]([C:23]4([C:26]5[CH:27]=[C:28]6[C:33](=[CH:34][CH:35]=5)[N:32]=[CH:31][CH:30]=[CH:29]6)[CH2:25][CH2:24]4)=[CH:21][N:22]=3)[CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](=[O:8])[N:45]1[CH2:46][CH2:51][CH2:50][CH2:49]1
Reactant: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Product: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenoxy}propanoic acid (59.1 mg, 0.126 mmol) in N,N-dimethylformamide (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (56 mg, 0.126 mmol), pyrrolidine (9.0 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.1 mL) at RT. The mixture was stirred at RT for 3 h, and then purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=522.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Whilst carrying out external cooling with ice water a solution of 44.3 g (0.2 mol) of 2-nitrobenzenesulphonyl chloride in 250 ml of chloroform was added dropwise to a solution of 38.0 g (0.2 mol) of 4-amino-1-(phenylmethyl)piperidine and 22.0 g (0.22 mol) of triethylamine in 250 ml of chloroform. After the cooling was stopped the mixture was stirred for a further 30 minutes at room temperature, the reaction mixture was then extracted twice with 1 l water. The aqueous extracts were extracted once more with 100 ml of dichloromethane, the combined organic phases were then dried over sodium sulphate and evaporated down in vacuo. The highly viscous light-brown substance obtained in a yield of 75.0 g (99.9% of theory) was further processed without any more purification.
Reaction SMILES: I.[NH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[N:9][NH2:10].Cl.[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>>[N:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:2]3[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]3=[N:9][N:10]=2)=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: NN=C1NCCCCN1
Agent: Cl
Agent: I
Product: c1cc(-c2nnc3n2CCCCN3)ccn1
Temperature: 160 °C
Yield: 207.3 %

Procedure:
A mixture of 1,3-diazepan-2-one hydrazone hydroiodide (1.00 g, 3.9 mmol) and isonicotinoyl chloride hydrochloride (695 mg, 3.9 mmol) was heated in a microwave reactor at 160° C. for 10 min. The reaction mixture was poured into NaaCO3 solution, sat., and extracted with DCM. The organic phase was dried and concentrated. Flash chromatography (DCM/MeOH 20:1) gave 1.74 g crude title compound which was used directly in the next step. 1H NMR: 1.89 (s, 4H) 3.15 (m, 2H) 3.86 (m, 2H) 7.44 (d, 2H) 8.66 (d, 2H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:23]=1.[CH2:40]1[O:42][CH2:41]1>O1CCCC1.O>[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:23]=1[CH2:40][CH2:41][OH:42]
Reactant: C1CO1
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: Cc1c(CCO)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To a solution of lithium diisopropylamide prepared from diisopropylamine (1.11 g) and n-butyllithium (1.61 M in hexane; 7.0 ml), in dry tetrahydrofuran under nitrogen atmosphere at -70° C. was added dropwise over 20 minutes a solution of 3-methyl-1-phenylsulfonylindole (2.71 g) in tetrahydrofuran (20 ml). The mixture was stirred for 1 hour below -70° C. and then allowed to warm slowly to 0° C. over 1 hour. The resulting solution was cooled to -70° C. and then treated with ethylene oxide (484 mg) in dry tetrahydrofuran (5 ml). The mixture was stirred for 1 hour below -70° C. and then allowed to warm slowly to room temperature over 3 hours. After stirring overnight, the reaction mixture was treated with cold water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel (eluted with 5% ethyl acetate in toluene) to give 2-[3-methyl-1-(phenylsulfonyl)indol-2-yl]ethanol (1.19 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.CCCCCC>C(OCC)(=O)C>[NH2:5][C:4]1[CH:3]=[C:2]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Nc1cccc(Br)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2cccc(N)c2)cc1
Yield: 42.9 %

Procedure:
Following the general procedure, 3-bromoaniline (56 μL, 0.5 mmol) was coupled with ethyl 4-aminobenzoate (125 mg, 0.75 mmol) with the reaction temperature of 80° C. and the reaction time of 17 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 55 mg (43%) of the title compound as a pale brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21]Br)[CH:9]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(CBr)cc2C1=O
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(CN3CCOCC3)cc2C1=O
Reaction time: 2 h
Yield: 16.1 %

Procedure:
6-Bromomethyl-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.1 g, 2.96 mmol) obtained in Step 5 was dissolved in N,N-dimethyl formamide. Pyridine (264 μl, 3.26 mmol) and morpholine (284 μl, 3.26 mmol) were added thereto, followed by stirring for 2 hrs. Upon the completion of the reaction, the resulting mixture washed successively with saturated ammonium chloride and saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 180 mg of the titled compound (yield: 16.1%) in red oil state.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([C:17](=[O:19])[CH3:18])[CH:9]=[CH:8]2.CO>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([C:17](=[O:19])[CH2:18][Br:1])[CH:9]=[CH:8]2
Reactant: COc1cc2ccc(C(C)=O)cc2cc1OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ccc(C(=O)CBr)cc2cc1OC
Yield: 66.9 %

Procedure:
A solution of bromine (4.5 g, 0.029 mol) in chloroform (30 ml) is added dropwise to a solution of 6,7-dimethoxy-2-acetylnaphthalene (6.7 g, 0.029 mol) in a mixture chloroform (70 ml)/methanol (15 ml). Once the reaction mixture discoloures, it is concentrated to dryness and the residue is treated with a mixture ethyl ether/isopropyl ether. The thus obtained solid is triturated with methanol yielding 6,7-dimethoxy-2-(2-bromoacetyl)naphthalene (6 g). M.p. 120°-122° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([F:22])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2].[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([F:22])[CH2:21][N:20]([CH2:33][C:34]([CH3:37])([OH:35])[CH3:36])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CNC3)n(C)c2n1
Reactant: CC1(C)CO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 80 °C
Yield: 21 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-fluoroazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (90 mg, 0.21 mmol) and 2,2-dimethyloxirane (1 mL) in IMS (2 mL) was heated to 80° C. for 24 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) then triturated with Et2O. The resulting residue was further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 5-95%) affording 839 (22 mg, 21%). LCMS (method I): RT 2.63 min, [M+H]+ 509.3. 1H NMR (DMSO, 400 MHz): δ 8.04-8.03 (1 H, m), 7.65-7.62 (1 H, m), 7.26-7.25 (2 H, m), 4.28 (4 H, brd s), 4.14 (2 H, dd, J=18.78, 9.71 Hz), 3.82-3.74 (9 H, m), 3.31-3.29 (4 H, m), 1.34 (3 H, t, J=7.43 Hz), 1.07 (6 H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH3:41]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH2:34][CH:35]3[CH2:39][CH2:38][CH2:37][N:36]3[CH2:40][CH3:41])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN1CCCC1CN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid 5.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs with a stream of nitrogen bubbling through it. The 2-(aminomethyl)-1-ethylpyrrolidine (4.46 g, 0.0348 mole) was added dropwise and the reaction mixture was allowed to stir at room temperature overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[C:10]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[CH:11]=O.C1(P(=[CH:46][CH:47]=[O:48])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[C:10]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[CH:11]=[CH:46][CH:47]=[O:48]
Reactant: Cc1ccc(C(=C(C=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=C(C=CC=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Yield: 89.9 %

Procedure:
A solution of 3,3-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (1.35 g, 3.8 mmoles) and triphenylphosphoranylidene acetaldehyde (1.16 g, 3.8 mmoles) in benzene was heated at reflux for 3 hours. The solvent was removed and the residue purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride. The fractions containing material having Rf =0.9 [methanol-methylene chloride; 1.20 (v/v)] were combined and concentrated to give 1.3 g of the title compound; m.p.=88°-108° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][CH2:18][C:19]2([C:22]([F:25])([F:24])[F:23])[CH2:21][O:20]2)[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]=2[CH:10]=1.[CH2:26]([NH2:28])[CH3:27]>O1CCCC1>[CH2:26]([NH:28][CH2:21][C:19]([CH2:18][NH:17][C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:20])[C:22]([F:24])([F:23])[F:25])[CH3:27]
Reactant: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccccc3)c2c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.9 %

Procedure:
To a solution of 6-methyl-1-phenyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine (1.1 g, 3.17 mmol) in anhydrous tetrahydrofuran (5 ml) was added ethylamine (2M in tetrahydrofuran) (10 ml, 20 mmol). The reaction was stirred at room temperature for 6 hours and then evaporated in vacuo to give the title compound (1.28 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25](OC1C=CC([N+]([O-])=O)=CC=1)=[O:26].[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]2[NH:48][C:47](=[O:49])[N:46]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:45][CH2:44][C:43]=2[CH:56]=1>>[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]2[NH:48][C:47](=[O:49])[N:46]([CH:50]3[CH2:55][CH2:54][N:53]([C:25]([O:22][C@@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C:12]4[CH:11]=[C:10]([CH3:23])[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:14]([CH3:15])[CH:13]=4)=[O:26])[CH2:52][CH2:51]3)[CH2:45][CH2:44][C:43]=2[CH:56]=1
Reactant: COC(=O)[C@H](O)Cc1cc(C)c(OCc2ccccc2)c(C)c1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(N2CCc3cc(OC)ccc3NC2=O)CC1

Procedure:
Prepared analogously to Example 21a from 1.41 g (3.63 mmol) methyl(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate, 0.75 g (3.63 mmol) 4-nitrophenyl chloroformate and 1.00 g (3.63 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH2:21][OH:22])=[C:19]([Cl:23])[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)#[N:2].[CH3:28][Sn:29]([N:32]=[N+:33]=[N-:34])([CH3:31])[CH3:30]>>[CH3:28][Sn:29]([CH3:31])([CH3:30])[N:32]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[C:20]([CH2:21][OH:22])=[C:19]([Cl:23])[N:18]=[C:17]3[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)=[N:2][N:34]=[N:33]1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Yield: 101.7 %

Procedure:
To a solution of 1-[(2'-cyano-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole (4.40 g, 0.011 mole) in xylenes (40.0 ml) was added trimethyltin azide (2.80 g, 0.014 mole), and the reaction was heated at 115°-120° for 40 hrs. The mixture was cooled to 50° and filtered to yield 1-{[2'-(N-trimethylstannyl-tetrazol-5-yl)-biphenyl-4-yl]methyl}-2-butyl-4-chloro-5-hydroxymethyl imidazole (6.55 g, 99%), m.p. 154°-160°; 1H NMR (CDCl3 /DMSO-d6) δ: 7.80-7.30 (m, 4H), 7.03 (q, 4H), 5.23 (s, 3H), 4.43 (s, 3H), 2.54 (t, 3H); 2.00 (s, 1H), 1.80-1.10 (m, 4H); 0.85 (t, 3H); 0.40 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21]O)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.CS([Cl:34])(=O)=O.O>ClCCl>[Cl:34][CH2:21][CH2:20][N:15]1[C:16](=[O:19])[CH2:17][CH2:18][N:12]([C:10](=[O:11])/[CH:9]=[CH:8]/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCO)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCCl)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 102.2 %

Procedure:
To an ice-cooled solution of 2.13 g (3.50 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-4-(2-hydroxy-ethyl)-[1,4]diazepan-5-one and 0.73 ml (5.25 mmol) of Et3N in 35 ml of dichloromethane were added 0.29 ml (3.68 mmol) of methanesulfonyl chloride under stirring within 5 min keeping the temperatue at 0° C. The reaction was stirred at room temperature for 1 h 45 min. Water was added and after 5 min, the reaction was then partitioned between ether and aqueous saturated NaHCO3. The water phase was extracted again with ether (2×), the organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and concentrated to yield 1.22 g (87%) of the title compound as yellow viscous oil. MS: 341.0 (MH+, 2Cl).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([Cl:11])[CH:3]=1.[NH:12]([C:14](=[S:16])[NH2:15])[NH2:13].P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:16][C:14]([NH2:15])=[N:12][N:13]=2)=[C:4]([Cl:11])[CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2ccc(Br)cc2Cl)s1
Temperature: 78 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To an ice-cooled mixture of 4-bromo-2-chlorobenzoic acid (3 g, 12.74 mmol) and hydrazinecarbothioamide (2.17 g, 23.81 mmol) was added phosphorous oxychloride (3.56 mL, 38.2 mmol) slowly. The mixture was heated at 78° C. overnight. After cooling to 0° C., ice water was added. The mixture was vigorously stirred for 1 h. The resulting precipitate was filtered and washed with water then re-suspended in a saturated NaHCO3 solution and water (1:1) for 1 h. The solid was filtered, washed with water, and concentrated in vacuo to give 5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (2.4 g, MS: 291.8 [M+H+].)
Reaction SMILES: C=O.N1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[CH3:13][CH2:14][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:4][CH2:5][O:6][C:7]([CH3:8])=[O:15]
Reactant: Oc1ccccc1
Reactant: C1COCCN1
Agent: C=O
Solvent: CCO
Product: CCCCCC
Product: CCOC(C)=O
Yield: 40 %

Procedure:
A solution of paraformaldehyde (3.24 g, 108 mmol) and morpholine (9.40 mL, 108 mmol) in ethanol (40 mL) was stirred at room temperature for 30 minutes, and then a solution of the corresponding phenol 6a, 6b (106 mmol) in 20 mL of ethanol was added and the mixture was refluxed overnight. After cooling, the solvent was evaporated, and the crude product 7a, 7b was purified by chromatography in silica gel, eluent hexane/EtOAc 9:1 (40-65% yield).
Reaction SMILES: N1C=CC=C(C=C[N:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])C=1>CO.C1COCC1.[Pd]>[N:9]1[CH:18]=[CH:17][CH:16]=[C:11]([CH2:12][CH2:13][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:19])[NH:9][CH:18]=2)[CH:10]=1
Reactant: O=c1c2ccccc2ccn1C=Cc1cccnc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]cc(CCc2cccnc2)c2ccccc12

Procedure:
80 g (322 mmol) of an (E/Z) mixture of 4-[2-(pyridin-3-yl)-vinyl-2H-isoquinolin-1-one in 3100 ml of methanol/THF 1:1 are hydrogenated in the presence of 15.2 g of Pd/C (10%). Filtration and concentration by evaporation yield the crude product. Recrystallisation by dissolving in 650 ml of boiling ethanol, hot filtration, cooling and addition of 1 l of diethylether and 0.2 l of hexane yield colourless 4-[2-(pyridin-3-yl)-ethyl]-2H-isochinolin-1-one; m.p. 187-188° C.
Reaction SMILES: [SiH3:1][SiH3:2].[CH:3]([NH:6][CH:7]([CH3:9])[CH3:8])([CH3:5])[CH3:4].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>[Ru]>[CH:3]([N:6]([SiH:1]([N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])[SiH3:2])[CH:7]([CH3:9])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)NC(C)C
Reactant: CCNCC
Reactant: [SiH3][SiH3]
Agent: [Ru]
Product: CCN(CC)[SiH]([SiH3])N(C(C)C)C(C)C
Temperature: 125 °C
Reaction time: 5 h

Procedure:
Diisopropylaminodiethylaminodisilane is synthesized in a pressurized reactor vessel by the reaction between disilane, diisopropylamine and diethylamine catalyzed by commercially available Ruthenium on carbon: A 0.3 L autoclave (reaction vessel) equipped with a mechanical stirrer, a thermocouple, a pressure gauge and a pressure transducer and 3 metering valves, as illustrated in FIG. 1, is charged with 6 g (0.003 mmol of ruthenium) of 5% weight ruthenium on carbon catalyst. The reactor is then heated under dynamic vacuum at 125° C. for 3 hr. activating the catalyst. After cooling to room temperature, the reactor is filled with helium at 1 atmosphere (“atm”) pressure, sealed and disconnected from the manifold. Inside a glove box, 20.7 g (0.205 mol) of diisopropylamine is added to the reactor. The reactor is taken out from the glove box and reconnected to the manifold and it is cooled to −130° C. in a liquid nitrogen bath. 30 g (0.453 mol) of disilane are transferred to the reactor through the manifold. The reactor is heated to about 150° C. The reactor contents is stirred at about 400 rpm for about 5 hr, pressure in the reactor increases about 160 psi. The reactor is cooled to RT. Volatiles are cryotrapped in a stainless steel lecture bottle (“SSLB”). The reaction vessel pressure drops to about 45 Torr. The reactor is put back in the glove box and is opened. 15.0 g (0.205 mol) of diethylamine are added to the mixture. They reactor is then heated to temperatures varying from about 30° C. to about 150° C. The reactor is stirred at about 400 rpm for about 2-24 hr. the pressure increases to about 160 psi. Volatiles are cryotrapped in a stainless steel lecture bottle (“SSLB”). The reaction vessel pressure drops to about 25-45 Torr. The diisopropylaminodiethylamino-disilane is recovered from the reaction vessel.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:9]2[C@@H:8]([NH2:12])[CH2:7][CH2:6][C:5]=2[N:4]=1.[CH:13]1([C:16]2[C:24]3[C:19](=[N:20][C:21]([O:28][CH2:29][C:30](O)=[O:31])=[CH:22][C:23]=3[CH:25]([F:27])[F:26])[N:18]([CH3:33])[N:17]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:13]1([C:16]2[C:24]3[C:19](=[N:20][C:21]([O:28][CH2:29][C:30]([NH:12][C@@H:8]4[C:9]5[C:5](=[N:4][C:3]([CH3:2])=[CH:11][CH:10]=5)[CH2:6][CH2:7]4)=[O:31])=[CH:22][C:23]=3[CH:25]([F:26])[F:27])[N:18]([CH3:33])[N:17]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2c(n1)CC[C@@H]2N
Reactant: Cn1nc(C2CC2)c2c(C(F)F)cc(OCC(=O)O)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)CC[C@@H]2NC(=O)COc1cc(C(F)F)c2c(C3CC3)nn(C)c2n1
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To the solution of (S)-2-methyl-6,7-dihydro-5H-[1]pyrindin-5-ylamine hydrochloride (75 mg, 0.41 mmol) and (3-cyclopropyl-4-difluoromethyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (building block A2, 110 mg, 0.37 mmol) in DMF (6 ml) were added DIPEA (0.26 ml, 1.48 mmol) and HATU (169 mg, 0.44 mmol) and the reaction was stirred at it for 3 h. The mixture was diluted with EtOAc, washed with aqueous bicarbonate solution and brine, dried over sodium sulfate, and the solvents were evaporated under reduced pressure. Purification by preparative HPLC (Gilson GX-281, Waters Sunfire C18, 5 μm, 30×100 mm with guard column 19×10 mm, solvent A: water with 0.1% TFA, solvent B: acetonitrile, gradient 10-30% B in 16 min, flow rate 50 ml/min) gave the title compound as off-white solid (115 mg, 72%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.61 (d, 1H), 7.47 (t, 1H), 7.36 (d, 1H), 6.99 (d, 1H), 6.93 (s, 1H), 5.32 (dd, 1H), 4.89 (s, 2H), 3.81 (s, 3H), 3.34 (s, 3H), 2.93-2.89 (m, 1H), 2.86-2.80 (m, 1H), 2.41 (s, 3H), 2.41-2.36 (m, 1H), 2.24-2.19 (m, 1H), 1.92-1.86 (m, 1H), 0.94-0.87 (m, 4H); LCMS RtI=3.032 min; [M+H]+=428.2]