Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Reactant: NCCc1ccc(N)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1

Procedure:
A solution of 4-chloro-7-(3-chloro-propoxy)-quinazoline (synthesized as reported in J. Med. Chem. 2007, 50, 2213-2224) (100 mg, 0.389 mmol), 2-(4-aminophenyl)ethyl amine (63.6 mg, 0.467 mmol) and triethylamine (118.1 mg, 1.167 mmol) in ethanol (3 mL) was heated at 120° C. for 3 hours. The solution was cooled and the solid formed was filtered, washed with ethanol and then with dichloromethane to give the title compound as light yellow solid product (34 mg, 25%). 1H-NMR (300 MHz, CD3OD): 7.93-8.37 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.07-7.13 (m, 2H), 7.00-7.03 (d, J=8.1 Hz, 2H), 6.66-6.69 (d, J=8.4 Hz, 2H), 4.24-4.28 (t, 2H), 3.71-3.81 (m, 4H), 2.84-2.89 (t, 2H), 2.27-2.31 (m, 2H). LC-MS (ESI) m/z 357.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[N:5]([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23](O)=[O:24].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:31][C:27]1[CH:28]=[C:29]([Br:30])[C:21]2[N:20]=[C:17]([C:4]3[N:5]([C:7]4[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH:6]=[C:2]([Br:1])[CH:3]=3)[O:19][C:23](=[O:24])[C:22]=2[CH:26]=1
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Reactant: O=C(O)c1cc(Br)cn1-c1ncccc1C(F)(F)F
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)cn2-c2ncccc2C(F)(F)F)nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-1-(3-trifluoromethyl-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4-bromo-1-(3-trifluoromethyl-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@H:8]([O:20][C@@H:21]2[C@@H:28]([CH2:29][O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:27][C@H:24]([O:25][CH3:26])[C@H:23]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:22]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:7]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:6]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=O)C.CO>C1(C)C=CC=CC=1.C[O-].[Na+]>[CH2:39]([O:38][C@@H:23]1[C@@H:22]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@H:21]([O:20][C@H:8]2[O:9][C@H:10]([CH2:11][O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:5]([OH:4])[C@H:6]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:7]2[O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@@H:28]([CH2:29][O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:27][C@@H:24]1[O:25][CH3:26])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galacto-pyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.543 g, 2.71 mmol) is dissolved in hot toluene (20 mL) and methanol (80 mL) is added, followed by a few drops of 1 M methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 2,3,6-tri-O-benzyl-4-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-α-D-glucopyranoside as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]4[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:26]=[CH:27][C:28]6[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=6[CH:35]=5)[CH2:20]4)[C:3]=1[C:4]=23.[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]4[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:26]=[CH:27][C:28]6[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=6[CH:35]=5)[CH2:20]4)[C:3]=1[C:4]=23
Reactant: O=C1CSc2ccc(N3C[C@H](CCCN[C@@H]4Cn5c(=O)cnc6ccc(F)c4c65)OC3=O)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1CSc2ccc(N3C[C@H](CCCN[C@@H]4CN5C(=O)CNc6ccc(F)c4c65)OC3=O)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of the compound of Example 79 (42 mg) in DCM/MeOH (2:1; 6 mL) was treated with NaBH4 (3.2 mg). After 30 min stirring at rt, the reaction mixture was quenched with 1M HCl (1 mL) and partitioned between DCM and aq. NH4OH. The org. layer was washed with water, dried over MgSO4, concentrated under reduced pressure and purified by CC (EA/MeOH 19:1 to 9:1), affording a beige solid (29 mg; 69% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:45])[CH2:40][CH2:41][CH2:42][NH:43][CH3:44]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:43]([CH2:42][CH2:41][CH2:40][N:39]([CH3:45])[CH3:38])[CH3:44])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(N(C)CCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N,N,N′-trimethyl-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) 1.70 (m, 2 H), 2.04 (m, 2 H), 2.20 (s, 6 H), 2.36 (s, 3 H), 2.89-3.21 (m, 3 H), 3.36-3.70 (m, 2H), 6.36 (d, J=8.4 Hz, 1 H), 7.16 (m, 1 H), 7.27 (m, 2 H), 7.50 (m, 2 H), 7.59 (m, 2H), 8.01 (s, 1 H), 8.13 (m, 1 H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:18].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:18][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Oc1ccc(Oc2cccc(Cl)c2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccc(Oc3cccc(Cl)c3)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a solution of 0.07 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.40 g of 2-chloro-4-(3-chlorophenoxy)phenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 10 minutes, a solution of 0.25 g of p-chlorobenzyl chloride in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.48 g of 4-chloro-1-[2-chloro-4-(3-chlorophenoxy)phenoxy]methylbenzene. Yield, 81%. m.p., 72.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH3:20])=[CH:5][CH:4]=1.CN1C2C(=C(C(N)C)C=CC=2)C=C1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19]([C:21]2[CH:22]=[CH:27][CH:26]=[C:25]3[C:30]=2[CH:29]=[CH:28][N:24]3[CH3:23])[CH3:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Agent: CC(N)c1cccc2c1ccn2C
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Product: COc1ccc(-c2cc(CNC(C)c3cccc4c3ccn4C)ccc2OC)cc1
Yield: 74 %

Procedure:
The title compound was prepared by the same procedure for (6,4′-dimethoxy-biphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from 1-(1-Methyl-1H-indol-4-yl)-ethylamine (522 mg, 3.0 mmol), 6,4′-Dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, hexane/ethyl acetate 3/2) in form as white solid in 74% yield (296 mg, 0.74 mmol).
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH3:36][O:37][CH2:38][CH2:39]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:39][CH2:38][O:37][CH3:36])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCN1CCC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 (300 mg, 0.59 mmol) in DMF (3.5 mL) was added 2-bromoethyl methyl ether (60 μL, 0.65 mmol) and potassium carbonate (285 mg, 2.07 mmol) and the reaction mixture stirred at 60° C. for 2 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate, then water followed by brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% MeOH in DCM) followed by trituration in cyclohexane to give 511 (187 mg, 70%). LCMS: RT=3.42 min, [M+H]+=454. 1H NMR 400 MHz (DMSO-d6) δ: 8.23 (1 H, d, J=8.19 Hz), 8.05 (1 H, s), 7.04 (1 H, dd, J=8.22, 1.79 Hz), 6.88 (1 H, d, J=1.74 Hz), 5.77-5.76 (1 H, m), 4.31 (2 H, t, J=5.00 Hz), 3.44-3.34 (5 H, m), 3.20 (3 H, s), 2.93 (3 H, d, J=10.98 Hz), 2.02 (2H, t, J=11.43 Hz), 1.71 (3 H, m), 1.64-1.53 (2 H, m), 1.50 (6 H, d, J=6.58 Hz)
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20][C:21](C)([O-])C.[K+].C(I)C.CN(C)C=O>O1CCCC1>[C:1]([C:3]1[N:7]([CH2:20][CH3:21])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC)cc1
Reaction time: 0.25 h
Yield: 11 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.160 g, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL). Potassium tert-butoxide (1.25 mL of a 1 M solution, 1.25 mmol) was dropwise added and the mixture stirred 15 minutes. Ethyl iodide (0.046 mL, 0.58 mmol) was dropwise added, followed by dimethyl formamide (5 mL) and the mixture stirred for 4 hours. The mixture was then partitioned between saturated ammonium chloride and ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated. The residue was purified by silica gel Flash Chromatography (hexane/ethyl acetate; 7:3) to afford the title compound (0.020 g, 11%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1[F:24])[CH:19]=O.[CH2:26]([CH2:28][NH2:29])[OH:27].[OH-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1[F:24])[CH2:19][NH:29][CH2:28][CH2:26][OH:27]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCCNCc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (14.1 g) was added to a solution of 3,4,5-trifluorobenzaldehyde (5.0 mL), ethanolamine (3.52 g), and acetic acid (10.1 mL) in THF (100 mL) under ice-cooling, and the reaction solution was stirred at room temperature for four hours and 30 minutes. Ice water was added to the reaction solution. The reaction solution was adjusted to pH 7 to 8 by a 5 N sodium hydroxide solution and saturated sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the mother liquor was concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:methanol=1:100 to 1:5) to obtain 6.91 g of the title compound.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=3)[CH2:2]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCN(Cc1ccc(Br)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
To a solution of methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride (500.0 mg, 2.00 mmol) in DMF (17.0 mL) was added 4-bromobenzylbromide (604 mg, 2.42 mmol) and K2CO3 (910 mg, 6.59 mmol). The resulting mixture was stirred overnight at rt. EtOAc and water were added, and the phases were separated. The organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography (SiO2, 0-40% EtOAc in hexane) to give methyl 2-(4-bromobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (753 mg, 100%). LC-MS: (FA) ES+ 361; 1H NMR (300 MHz, CDCl3) δ 7.86-7.70 (m, 2H), 7.46 (dd, J=8.7, 2.1 Hz, 2H), 7.36-7.21 (m, 2H), 7.04 (d, J=8.0 Hz, 1H), 3.89 (d, J=3.8 Hz, 3H), 3.64 (s, 4H), 2.93 (t, J=5.8 Hz, 2H), 2.83-2.64 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:3][O:4][CH3:5]>C(O)(=O)C.[Pt](=O)=O>[CH3:6][C:2]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)([CH3:1])[CH2:3][O:4][CH3:5]
Reactant: COCC(C)(C)c1ccncc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COCC(C)(C)C1CCNCC1
Reaction time: 41 h
Yield: 93.6 %

Procedure:
A solution of 4-(1,1-dimethyl-2-methoxyethyl)pyridine (10.0 g) in acetic acid (120 ml) was catalytically hydrogenated over platinum dioxide at 40 p.s.i. for 41 hours at from ambient temperature to 43° C. After 24 hours a further quantity of platinum dioxide was added, and a final addition was made after a further 8 hours. After a total of 41 hours the solution obtained after filtration of the catalyst was evaporated in vacuo and further evaporated after the addition of toluene to remove acetic acid. The resultant yellow oil was dissolved in dichloromethane and brought to pH12 with dilute aqueous sodium hydroxide solution. After saturation with sodium chloride, the organic phase was separated and the aqueous layer was re-extracted with five portions of dichloromethane. The combined organic solution was dried over anhydrous magnesium sulphate, and evaporated in vacuo to give 4-(1,1-dimethyl-2-methoxyethyl)piperidine (9.7 g) as a straw-coloured oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])(=[O:19])=[O:18])[CH3:15])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([CH:14]([CH3:15])[N:16]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH3:29])(=[O:19])=[O:18])[C:4]=2[CH:3]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3cc(Cl)ccc3-c3ccccc3C2C)c(OC)c1

Procedure:
The title compound was prepared from N-[1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethyl]-2,4-dimethoxybenzenesulfonamide (470 mg, 1.04 mmol), anhydrous N,N-dimethylformamide (2 mL), and potassium carbonate (287 mg, 2.0 mmol) according to the procedure and in the same manner as described in Example 105, step d resulting in the isolation of 447 mg (100%) of a white solid that was used without further purification;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][OH:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C.CNC1C=CN=CC=1>C(Cl)Cl.C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: OCc1cc2ccc(Br)cc2c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CNc1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc2ccc(Br)cc2c2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
To a solution of 3-bromo-9-(hydroxymethyl) phenanthrene, 4 (5.96 g, 20.8 mmol) and t-butyldimethylsilyl chloride (4.7 g, 31 mmol) in 100 ml of CH2Cl2 and 20 ml of THF was added triethylamine (4.9 ml, 35 mmol) followed by 4-methylaminopyridine (250 mg, 2.05 mmol). After stirring at room temperature for 20 hours, the solution was poured into 300 ml of ethyl ether and washed successively with sat. NH4Cl, sat. NaHCO3, H2O, and brine. Drying (Na2SO4) and evaporation gave a brown solid which was purified by flash chromatography through 400 g of silica gel (1:4 CH2Cl2 -hexane) to yield 7.23 g (87%) of the title compound as a pale yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28])(C(C)(C)C)(C)C.Cl>C(O)C>[NH2:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][O:26][CH2:27][CH3:28])[N:11]([CH2:10][CH2:9][OH:8])[C:23]=2[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CCO
Reaction time: 2 h
Yield: 139.7 %

Procedure:
1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.93 g, 4.81 mmol) was dissolved in 20 mL of ethanol and treated with 1.6 mL of 3 M HCl in ethanol and the mixture was heated to reflux. After 2 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between 50 mL of CHCl3 and 25 mL of dilute NH4OH solution. The layers were separated and the aqueous portion was extracted with additional CHCl3 (12×20 mL). The combined organic portions were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 25% CMA/CHCl3) gave 2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]ethanol (1.93 g) as a light-yellow powder.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)O1.Br[C:29]1[CH:30]=[C:31]([CH2:35][OH:36])[CH:32]=[CH:33][CH:34]=1.COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:21]1([C:18]2[CH:17]=[CH:16][C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][OH:36])[CH:30]=3)=[CH:20][CH:19]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: OCc1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCc1cccc(-c2ccc(N3CCOCC3)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium (36 mg) and sodium carbonate (330 mg) were added to a mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (300 mg), (3-bromophenyl)methanol (233 mg), DME (6 ml), and water (3 ml), followed by stirring at 80° C. overnight, and then the reaction mixture was concentrated under reduced pressure. Water and CHCl3 were added to the obtained residue, and the organic layer was dried over MgSO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/CHCl3) to obtain [4′-(morpholin-4-yl)biphenyl-3-yl]methanol (242 mg).
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[N:12][CH:11]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:13]4[CH:14]=[CH:15][N:10]=[CH:11][N:12]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Reactant: NCc1ccncn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ccncn1
Yield: 65 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyrimidin-4-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 65% yield: mp 188-191° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 8.68 (d, J=5.1 Hz, 1H), 7.33 (d, J=4.9 Hz, 1H), 6.89-6.87 (m, 1H), 4.69 (d, J=5.0 Hz, 2H), 4.16-4.11 (m, 2H), 3.74-3.69 (m, 2H), 3.20 (d, J=7.1 Hz, 2H), 2.64 (s, 3H), 1.00-0.91 (m, 1H), 0.61-0.55 (m, 2H), 0.28-0.23 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.0, 162.8, 158.5, 157.9, 156.9, 155.2, 153.2, 119.1, 117.1, 48.6, 44.1, 42.2, 42.1, 17.3, 8.9, 3.5; MS (ES+) m/z 373.2 (M+1).