Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:34]5[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)cn1
Temperature: 120 °C
Yield: 71.5 %

Procedure:
N-(1-Bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (268 mg, 0.600 mmol) was dissolved in 6 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 6-Methoxypyridin-3-ylboronic acid (119 mg, 0.780 mmol), 0.6 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 34.7 mg, 0.0300 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The crude product was evaporated to dryness and then purified on silica gel utilizing a gradient of 0-50% ethyl acetate in hexanes to yield 1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)-N-(1-(6-methoxypyridin-3-yl)isoquinolin-3-yl)cyclopropane-carboxamide (204 mg, 71%). ESI-MS m/z calc. 475.1. found; 476.3 (M+1)+ Retention time 2.31 minutes.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:21][NH2:22]>>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[C:15]([OH:17])=[N:21][NH:22][C:11]=2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Product: Oc1n[nH]c2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (10.0 g, 34 mmol, Aldrich) and hydrazine (30 mL, 824 mmol, Aldrich) was stirred at RT for 48 h. The volatile solvents were removed in vacuo, and the residue was azeotroped with MeOH (1×), then recrystallized from MeOH to obtain the title compound MS (ESI, pos. ion) m/z: 230 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
According to the synthesis scheme shown above, a mixture of indole-2-carboxylic acid (98 mg, 0.61 mmol, purchased from ACROS Co.), 10 ml benzene and thionyl chloride (SOCl2) (224 ml, 3.1 mmol) was placed in a 50 ml round-bottom flask purged with nitrogen gas and refluxed for 2 h while stirring, followed by cooling to room temperature. The mixture was concentrated to dry within a concentrator under a reduced pressure, and after the addition of 10 ml benzene, the mixture was concentrated again. Excess thionyl chloride (SOCl2) was removed from the mixture by three repeats of adding 10 ml benzene and concentrating the mixture, thus obtaining the title compound in the form of a yellow solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>C1COCC1>[CH2:14]([C:11]1[S:10][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:8])=[C:13]([B:27]([OH:28])[OH:26])[CH:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCc1ccc(S(=O)(=O)NC(C)(C)C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
5-Butylthiophene-2-sulfonic acid tert-butylamide (2.9 g, 0.010 mol, see step (a) above) was dissolved in THF (40 mL) under N2 and then cooled to −78° C. n-BuLi (1.6 M, 16.2 mL, 0.026 mol) was added via a syringe. The reaction mixture was stirred at −20° C. for 4 hours. Tri-iso-propylborate (13.3 mL, 0.058 mol) was then added via a syringe and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with 2 M HCl (20 mL). The organic phase was separated and the water phase was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine and dried and concentrated in vacuo. The product was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-:13].[Na+].Cl>CS(C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([OH:13])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: [OH-]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(O)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95.1 %

Procedure:
Step A To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80° C. for 20 h. The mixture was cooled to room temperature, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH2:13][C:14]2([NH2:17])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:17][C:14]1([CH2:13][C:12]2[CH:18]=[CH:19][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:16][CH2:15]1
Reactant: NC1(Cc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: NC1(Cc2ccc(O)cc2)CC1

Procedure:
Hydrogenation of 5.00 g (19.7 mmol) 1-(4-benzyloxy-benzyl)-cyclopropylamine in 60 mL methanol at 3 bar with palladium on charcoal as catalyst. Yield: 2.25 g (70%); mass spectroscopy: [M+H]+=164.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]([C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1Cl)=[O:7].Cl.[C:17]([O-])(O)=[O:18].[Na+]>C1COCC1.CCOC(C)=O>[CH3:4][O:5][C:6]([C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[O:18][CH3:17])=[O:7]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1nnc(Cl)cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (25 wt % I methanol, 1.1 mL) is added to a stirred solution of 4,6-dichloro-pyridazine-3-carboxylic acid methyl ester (1.03 g, 5 mmol) in THF (25 mL) cooled to 0° C. The reaction mixture is stirred at room temperature overnight and then poured into 1N HCl (8 mL). The resulting solution is then neutralized by saturated NaHCO3. EtOAc (20 mL) is added and the layers are separated. The aqueous layer is extracted twice with EtOAc (20 mL) and the combined extracts are washed with brine (25 mL), dried (Na2SO4) and evaporated. The residue is then purified by flash column chromatography (silica gel, eluted with 2:1 Hexane:EtOAc) to give 6-chloro-4-methoxy-pyridazine-3-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10](=[O:24])[NH:11][C:12](=[O:23])[N:13]([CH:22]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)=[O:4].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>CN(C=O)C>[Si:27]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[C:9]([C:8]#[C:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:26])[C:10](=[O:24])[NH:11][C:12]2=[O:23])[CH2:15][C@@H:16]1[OH:17])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1) (656 mg, 1.74 mmol) in dry DMF (15 ml) was added t-butyldimethylsilylchloride (288 mg, 1.91 mmol) in small portions, followed by imidazole (130 mg, 1.91 mmol). The reaction was followed by TLC and was completed after stirring for 8 h at room temperature. The reaction was quenched with sat. aq. NaCl solution. EtOAc (25 ml) was added to the reaction mixture and the aqueous layer was extracted with EtOAc three times. After drying the combined organics (MgSO4), the solvent was removed under vacuum. Purification by chromatography on silica (EtOAc:petroleum ether 8:2) gave (2) as slightly yellow crystals (676 mg, 83%). 1H NMR (d6 DMSO) δ 0.00 (s, 6H, CH3), 0.79 (s, 9H, tBu), 1.93-2.00 (m, 1H, H-2′), 2.06-2.11 (m, 1H, H-2′), 3.63-3.75 (m, 2H, H-5′), 3.79-3.80 (m, 1H, H-4′), 4.12-4.14 (m, 3H, H-3′, CH2N), 5.22 (d, J=4.1 Hz, 1H, OH), 6.03 (t, J=6.9 Hz, 1H, H-1′), 7.86 (s, 1H, H-6), 9.95 (t, J=5.4 Hz, 1H, NH), 11.61 (br s, 1H, NH). Mass (−ve electrospray) calcd for C20H28F3N3O6Si 491.17. found 490.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]2>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]2
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2c(O)cccc2[nH]1
Temperature: -78 °C
Yield: 64 %

Procedure:
Boron tribromide (73.1 ml, 1.0 M solution in DCM) was added dropwise to a solution of methyl 4-methoxyindole-2-carboxylate (5 g) in DCM (200 ml) cooled to −78° C. under argon. The reaction was allowed to warm to room temperature then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using iso-hexane-50% ethyl acetate as eluent to give the end product as a yellow solid (2.98 g, 64%); NMR d (CD3SOCD3) 3.82 (s, 3H), 6.36 (d, 1H), 6.85 (d, 1H), 7.02 (t, 1H), 7.17 (d, 1H), 9.66 (s, 1H), 11.72 (bs, 1H); M/z (+) 192 (MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH:15]([CH3:19])[CH2:16][CH2:17]O)[CH2:10]3)=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O.[OH-].[Na+].ClCCl>C(Cl)(Cl)Cl>[Cl:24][CH2:17][CH2:16][CH:15]([N:11]1[CH2:12][C@H:13]2[C@:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=3)([CH2:14]2)[CH2:10]1)[CH3:19]
Reactant: CC(CCO)N1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(CCCl)N1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
To a solution of 3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}-1-butanol (Preparation 19, 130 mg) in chloroform (4 mL), thionyl chloride (0.87 mmol) was added and the mixture was stirred at room temperature for 6 h. After addition of NaOH (1 M), dichloromethane was added and the organic layer was washed with Brine and dried over Na2SO4. The solution was concentrated in vacuo and the crude product purified by flash chromatography (ethyl acetate: cyclohexane=5:95) to give 106 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)(=[O:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:25][C:26]1([CH3:50])[CH2:35][CH2:34][C:33]2[N:32]=[CH:31][N:30]=[C:29]([N:36]3[CH2:42][C:41]4[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:40]=4[O:39][CH2:38][CH2:37]3)[C:28]=2[CH2:27]1>>[NH2:17][C@H:14]1[CH2:15][CH2:16][N:12]([S:9]([C:4]2[C:5]([OH:8])=[N:6][CH:7]=[C:2]([C:44]3[CH:45]=[CH:46][C:40]4[O:39][CH2:38][CH2:37][N:36]([C:29]5[C:28]6[CH2:27][C:26]([CH3:25])([CH3:50])[CH2:35][CH2:34][C:33]=6[N:32]=[CH:31][N:30]=5)[CH2:42][C:41]=4[CH:43]=3)[CH:3]=2)(=[O:10])=[O:11])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cc(Br)cnc2O)C1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(O)c(S(=O)(=O)N6CC[C@H](N)C6)c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 1,1-dimethylethyl {(3S)-1-[(5-bromo-2-hydroxypyridin-3-yl)sulfonyl]pyrrolidin-3-yl}carbamate (reagent preparation 40) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.53 (d, 2H), 8.00 (s, 1H), 7.57 (s, 1H), 7.41 (d, 1H), 7.03 (d, 1H), 5.12 (s, 2H), 4.45 (m, 1H), 4.29 (m, 1H), 3.93 (m, 1H), 3.72 to 3.55 (m, 6H), 2.85 (t, 2H), 2.56 (s, 2H), 2.35 (m, 1H), 2.06 (m, 1H), 1.69 (t, 2H), 0.93 (s, 6H); MS (EI) for C28H34N6O4S: 551 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23])([O-:14])=[O:13]>>[F:21][C:19]1[CH:18]=[CH:17][C:16]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:24])=[O:23])=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Product: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 105.6 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-aminoquinoline (500 mg, 3 mmol) and 2-nitro-4-fluorobenzenesulfonyl chloride (Intermediate 220) (914 mg, 4 mmol) gave the title compound (1.10 g, 91%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH2:18]([CH:20]([C:23]1[C:24]2[N:25]([CH:30]=[C:31]([CH3:33])[N:32]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:21][CH3:22])[CH3:19]>>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:30]3[N:25]4[N:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH:20]([CH2:18][CH3:19])[CH2:21][CH3:22])[C:24]4=[N:32][C:31]=3[CH3:33])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)nc12
Yield: 44.8 %

Procedure:
Using a procedure analogous to Example 16B, 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.10 g, 0.29 mmol) and 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.064 g, 0.29 mmol) give the title compound (0.054 g, 0.13 mmol, 43%). 1H NMR (CDCl3): δ 0.91 (t, J=7.5 Hz, 6H), 0.92 (t, J=7.0 Hz, 6H), 1.80-1.93 (m, 8H), 2.43 (s, 6H), 2.47 (s, 6H), 3.36-3.44 (m, 2H), 6.68 (s, 2H). ES-MS (m/z): calcd for C26H36N6 (M+H)+: 433.6. found: 433.3.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Yield: 68.3 %

Procedure:
Using the procedure described in Example 1, Part E, 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (1.56 g, 6.2 mmol) was treated with 248 mg (6.2 mmol) of 60% NaH/mineral oil and then 0.6 mL (6.2 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.37 g (69% yield) of [[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 89-92° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[CH:3]=1.[NH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20]>CCOC(C)=O>[NH2:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:3]=1
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CC(=O)NCCN
Solvent: CCOC(C)=O
Product: CC(=O)NCCNc1cc(N)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of chloroarene 4 (20.57 g; 0.100 mol) in N-(2-aminoethyl)-acetamide (71.05 g; 0.696 mol) was heated from 60 to 120° C. over 20 min then kept at 120° C. for 4.0 h. After cooling to rt, the reaction was diluted with EtOAc (500 mL) then washed with water (1×150 mL). The aq phase was extracted with EtOAc (3×25 mL) and the combined organic portions were washed with water (2×25 mL) and saturated NaCl (2×50 mL). The solution was dried (MgSO4), filtered then concentrated in vacuo to 21.34 g of an off-white hard foam. The product was purified in two batches on silica gel (1.7 L total) using 15-8:1 DCM:MeOH yielding a hard white foam (15.36 g; 57%). LC (method B) tR=5.5 min; 1H NMR (200 MHz, CDCl3) δ 8.29 (m, 2H), 7.43 (m, 3H), 6.71 (brs, 1H), 5.41 (s, 1H), 5.12 (brt, J=5.4 Hz, 1H), 4.68 (brs, 2H), 3.53 (m, 1H), 3.45 (m, 1H), 1.83 (s, 3H); ESIMS 272.03 (100) [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)=[O:23].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CC1(NC(=O)OCc2ccccc2)COC1)OCC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 106.9 %

Procedure:
(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 1.011 Kg, 3.812 mol) was stirred in ethyl acetate (8 L). 2-Bromo-1-[4-(trifluoromethoxy)phenyl]-ethanone (1.08 Kg, 3.81 mol) was added, followed by triethylamine (585 mL, 4.19 mol). The reaction was initially fully solubilised, but a precipitate was then observed. The reaction was washed with water (2×4 L), then concentrated in vacuo to afford the title compound as a mobile orange oil (1.903 Kg, 107%, contains residual ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:19][C:32](=[O:33])[O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: NCC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2O1)OCc1ccccc1
Yield: 90.7 %

Procedure:
Treatment of (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (1.8 g, 6.14 mmol) with diisopropylethylamine (1.06 g, 8.20) and benzyl chloroformate (1.12 g, 6.56 mmol) generally according to the procedure described for Intermediate 12 afforded 2.38 g (91%) of (±)-benzyl {7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a white solid. Rf=0.48 (silica, ethyl acetate:hexanes 1:4); mp 100-102° C.; Anal. calcd. for C24H20F3NO3: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.37; H, 4.69; N, 3.15.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH2:10])[C:3]=1[NH2:11].C(Cl)CCl.[CH:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.ClCCl>[NH2:11][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[C:4]=1[NH:10][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:16]([CH3:17])[CH3:18])=[CH:20][CH:21]=1
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(Br)c(N)c1N
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(Br)c(N)c1NC(=O)c1ccc(C(C)C)cc1
Yield: 98.9 %

Procedure:
A solution of 870 mg (4.01 mmol) 3-bromo-6-methoxy-benzene-1,2-diamine, 1.16 g (6.0 mmol) EDC, 744 mg (6.0 mmol) DMAP and 707 mg (4.01 mmol) 4-isopropylbenzoic acid in 20 ml dichloromethane is stirred at room temperature for 72 h. The reaction mixture is concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 1.44 g of the title compound as a slightly reddish solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:31])[CH2:17][C:16]2[NH:15][C:14]3[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11][C:10](=[O:20])[C:9]=3[CH:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[C:7]=2[C:6](=[O:30])[CH2:5]1.Cl[C:33]([O:35][CH3:36])=[O:34]>O1CCCC1.CN(C)C=O>[CH3:19][C:12]1([CH3:18])[CH2:13][C:14]2[N:15]([C:33]([O:35][CH3:36])=[O:34])[C:16]3[CH2:17][C:4]([CH3:31])([CH3:3])[CH2:5][C:6](=[O:30])[C:7]=3[CH:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[C:9]=2[C:10](=[O:20])[CH2:11]1
Reactant: COC(=O)Cl
Reactant: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)N1C2=C(C(=O)CC(C)(C)C2)C(c2ccc([N+](=O)[O-])cc2)C2=C1CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry of 17 mg of sodium hydride (80% dispersion in mineral oil) in 10 ml of anhydrous tetrahydrofuran was stirred at room temperature under an atmosphere of dry nitrogen and treated dropwise with a solution of 200 mg of 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8(2H,5H)-acridinedione in 5 ml of dimethylformamide. The mixture was then heated at reflux for 15 minutes, cooled to room temperature, treated with 44 ml of methyl chloroformate and stirred at room temperature under an atmosphere of dry nitrogen for 18 hours. The solvents were removed under reduced pressure and the resulting waxy residue was taken up in diethyl ether and the insoluble material was filtered off. The filtrate was then purified by column chromatography on silica gel using hexane/ethyl acetate (gradient: 80:20 to 50:50) as the eluent to give methyl 2,3,4,5,6,7,8,9-octahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8-dioxo-1H-acridine-10-carboxylate as a white crystalline solid of melting point 189-190° C.