Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:37]1[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CC(C)(C)OC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 15 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of tert-butyl piperazine-1-carboxylate as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[S:15][C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[CH3:1][C:2]1[S:15][C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH:3]=1)=[CH:11][C:10]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][CH:8]=3
Reactant: Cc1cn2c(=O)c3ccccc3nc2s1
Reactant: O=S(=O)(O)Cl
Product: Cc1cn2c(=O)c3cc(S(=O)(=O)Cl)ccc3nc2s1
Reaction time: 12 h

Procedure:
15 parts of 2-methyl-5H-thiazolo[2,3-b]quinazolin-5-one were introduced slowly into 70 parts of chlorosulfonic acid, at 20°-30° C. Stirring was continued for 12 hours, and the 2-methyl-7-chlorosulfonyl-5H-thiazolo[2,3-b]quinazolin-5-one formed was precipitated with ice water.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9].C([O-])(O)=O.[Na+]>ClCCl>[NH2:27][CH2:26][CH2:25][CH2:24][N:21]1[CH2:20][CH:19]=[C:18]([C:14]2[CH:13]=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)Nc1cccc(C2=CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C2=CCN(CCCN)CC2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1:1 solution of TFA:CH2Cl2 (5 mL) was added to tert-butyl N-(3-{4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinyl}propyl)carbamate in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 1-3 days, saturated NaHCO3 was added until pH>6, the organic layer was separated, and dried in vacuo, giving the desired product (45 mg): 1H NMR (CDCl3) δ 7.68 (br, 1H), 7.35 (dm, 1H, J=7.8 Hz), 7.25 (apparent t, 1H, J=7.8 Hz), 7.15 (dm, 1H, J=7.8 Hz), 6.12 (m, 1H), 3.22 (m, 2H), 3.03 (t, 2H, J=7.3 Hz), 2.78 (t, 2H, J=5.5 Hz), 2.70-2.50 (m, 4H), 2.10 (s, 3H), 1.87 (p, 2H, J=7.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: NCCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenylethylamine.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[OH-].[Li+]>>[C:26]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:17]([C@H:19]3[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]3)=[O:18])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(c1ccccc1)C(=O)[C@H]1CC[C@H](C)CC1
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1CC[C@H](C(=O)N(c2ccccc2)c2cc(C3=CCCCC3)sc2C(=O)O)CC1

Procedure:
The product from Step II (38 mg, 0.09 mmol) was hydrolysed with lithium hydroxide as previously described (example 3, step VIII) to give 32 mg (89%) of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-phenyl-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].CC(P(OC)(O)=O)(C([O-])=O)C.[F:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O.[C:25]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:27][CH2:28]C)=[O:26].[Cl-].[NH4+]>O1CCCC1>[CH3:28][O:27][C:25](=[O:26])[CH:30]=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[F:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)c(F)c1
Agent: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(OC)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 203.1 %

Procedure:
Sodium hydride (60% in mineral oil, 3.11 g, 77.86 mmol) is suspended in dry tetrahydrofuran (160 mL) and cooled to 0° C. Trimethylphosphonoacetate (14.18 g, 77.86 mmol) is added and the mixture stirred at 0° C. for 30 minutes. 2-Fluoro-4-methoxybenzaldehyde (10 g, 64.88 mmol) is added and the mixture stirred overnight at room temperature. (Carbethoxymethylene)triphenylphosphorane (11.3 g, 32.44 mmol) is added and the mixture stirred for 3 hours. Saturated aqueous ammonium chloride solution is added and the mixture extracted with ethyl acetate. The organic phase is dried and the solvent removed under vacuum. The residue is purified by flash chromatography (5% ethyl acetate in cyclohexane) to give the title compound (yield 13.85 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[C:7]#[N:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(N(CC)CC)C>[CH3:9][S:10]([O:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[C:7]#[N:8])(=[O:12])=[O:11]
Reactant: N#CC1COCC1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1COC[C@H]1C#N
Yield: 89.3 %

Procedure:
The title compound is prepared by the procedure of Example 178 using 0.367 g of product from Example 197, 0.394 g of triethylamine, and 0.446 g of methanesulfonyl chloride to give 0.554 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: CNOC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(F)ccc1Br
Reaction time: 1 h
Yield: 73 %

Procedure:
2-Bromo-5-fluorobenzoic acid (4.60 g, 0.02 mol), N,O-Dimethylhydroxylamine hydrochloride (2.05 g, 0.02 mol), carbon tertabromide (6.9 g, 0.02 mol) was added to mixture of methylene chloride (100 mL) and triethylamine (2.9 mL, 0.02 mol). Triphenylphospine (5.53 g, 0.02 mol) was added to the solution over 1 hour and stirred for another 1 hour. The solution was concentrated to an oil. Hexanes (100 mL) and Ethyl Acetate (100 mL) were added to the oil and stirred for 1 hour then filtered. The filtrate was concentrated and the residue was purified by chromatography (Hexanes/Ethyl Acetate) on silica gel to afford 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide as a foamy white solid in 73% yield. 1H NMR (CDCl3, 500 MHz) δ3.00-3.98 (m, 6 H), 6.97-7.08 (m, 2H), 7.51-7.54 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](I)[CH:8]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C1([O-])C=CC=CC=1.[K+].C([O-])(O)=O.[Na+]>CS(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH:8]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(I)ccc2n1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CS(C)=O
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(-c3ccccc3Cl)ccc2n1
Reaction time: 1 h
Yield: 63 %

Procedure:
To (2-Chloro-6-iodo-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (100 mg, 0.243 mmol) and 2-chlorophenyl boronic acid (57 mg, 0.364 mmol) in DMSO (5 mL, purged with Ar) was added 1.5M potassium phenolate solution (648 μL, 0.97 mmol) and 1,1′bis(diphenylphosphino)ferrocene palladium chloride, complex with dichloromethane (27 mg) and the solution was heated to 60 C in a sealed tube. After 1 hr, solution was poured into sat. NaHCO3 resulting in a yellow solid that was colleted by filtration. Flash chromatography (1-4% methanol in dichloromethane) to give: 73 mg (63% yield). LCMS m/e: 396.2 (M+H), 394.2 (M-H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[F:11].[O:12]1C[CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:15][CH:14]([CH2:13][OH:12])[O:8][N:7]=2)=[CH:4][C:3]=1[F:11]
Reactant: C1CCOC1
Reactant: ON=Cc1ccc(Br)c(F)c1
Product: OCC1CC(c2ccc(Br)c(F)c2)=NO1
Reaction time: 4 h

Procedure:
4-Bromo-3-fluoro-benzaldehyde oxime (55.7 g, 265.3 mmol) and ally alcohol (44 ml) were added to tetrahydrofuran (300 ml) and then bleach (1791 ml) was added. The reaction was stirred for four hours followed by extraction with tetrahydrofuran (2×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (66 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.Cl[CH2:16][CH2:17][N:18]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:20]Cl>>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][N:1]1[CH2:20][CH2:19][N:18]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[O:28][CH2:27][CH2:26][CH2:25]3)[CH2:17][CH2:16]1
Reactant: ClCCN(CCCl)c1ccc2c(c1)CCCO2
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Product: COc1ccc2[nH]cc(CCN3CCN(c4ccc5c(c4)CCCO5)CC3)c2c1

Procedure:
Analogously to Example 5, reaction of 3.2 g of 3-(2-aminoethyl)-5-methoxyindole with 1.3 equivalents of 6-[N,N-bis(2-chloroethyl)amino]chroman [obtainable by reaction of 2-chloroacetyl chloride with 6-aminochroman and subsequent reduction with diborane] gives 1-[2-(5-methoxyindol-3-yl)ethyl]-4-(chroman-6-yl)piperazine.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C1COCC1>[CH3:19][S:20]([O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1ccc(COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a solution of (4-propylphenyl)methanol (116 mg, 0.770 mmol) in THF (5 mL) were added triethylamine (0.220 mL, 1.54 mmol) and methanesulfonyl chloride (89.0 mL, 1.16 mmol), and the mixture was stirred at room temperature for 15 min. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (176 mg, quantitative). This was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH:57](O)([CH3:59])[CH3:58]>>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH:57]([CH3:59])[CH3:58])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: CC(C)O
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(COC(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1

Procedure:
Reactions similar to those of Reference Example 21 were performed except for using isopropanol instead of ethanol, and from 78 mg (0.10 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 17, 54 mg of the title compound was obtained as a foam (yield: 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1)([O-:3])=[O:2].C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CC#N>[CH3:24][N:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[CH2:8][O:7][C:6]1[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC[C@@H]1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) was dissolved in CH3CN (20 mL) and formaldehyde (2.4 mL, 37% aqueous) was added. NaBH3CN (607 mg) was added, an exotherm was observed. The pH was monitored every 15 min and adjusted to ˜7 with AcOH. After 45 min, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with 6 N NaOH, 1 N NaOH, and 2 N HCl (3×). The acid washings were combined, adjusted to ˜pH 10 with solid Na2CO3 and extracted with EtOAc (2×). The EtOAc fractions were combined, dried with Na2SO4, and purified with flash chromatography (SiO2, 95:5:0.5 CH2Cl2:MeOH:NH4OH) to afford the title compound.
Reaction SMILES: N#N.Cl[C:4]1[N:5]=[N+:6]([O-:19])[C:7]2[C:16]([N:17]=1)=[CH:15][C:14]1[CH2:13][N:12]([CH3:18])[CH2:11][CH2:10][C:9]=1[CH:8]=2.[Sn](CC)(CC)(CC)[CH2:21][CH3:22]>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>[CH2:21]([C:4]1[N:5]=[N+:6]([O-:19])[C:7]2[C:16]([N:17]=1)=[CH:15][C:14]1[CH2:13][N:12]([CH3:18])[CH2:11][CH2:10][C:9]=1[CH:8]=2)[CH3:22]
Reactant: CC[Sn](CC)(CC)CC
Reactant: CN1CCc2cc3c(cc2C1)nc(Cl)n[n+]3[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Temperature: 85 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Pd(PPh3)4 (350 mg, 0.3 mmol) was added to a N2-purged, stirred solution of chloride 257 (750 mg, 3.0 mmol) and Et4Sn (1.2 mL, 6.0 mmol) in DME (35 mL), and the mixture was stirred at 85° C. for 18 h under N2. The solution was cooled to 20° C. and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1-oxide 260 (590 mg, 81%) as a brown solid: mp 129-131° C.; 1H NMR δ 8.21 (s, 1H, H-10), 7.63 (s, 1H, H-5), 3.79 (s, 2H, H-6), 3.16 (t, J=6.0 Hz, 2H, H-8), 3.02 (q, J=7.6 Hz, 2H, CH2), 2.77 (t, J=6.0 Hz, 2H, H-9), 2.51 (s, 3H, NCH3), 1.43 (t, J=7.6 Hz, 3H, CH3); 13C NMR δ 167.3, 145.8144.6, 138.2, 131.7, 125.0, 118.8, 58.1, 52.3, 45.9, 30.7, 29.6, 12.2; MS (APCI) m/z 245 (MH+, 100%). Anal. calcd for C13H16N4O.¼H2O: C, 62.5; H, 6.7; N, 22.4. Found: C, 62.6; H, 6.6; N, 22.4%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>>[CH3:25][S:22]([CH2:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:3][C:2]([C:36]4[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19])(=[O:24])=[O:23]
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CS(=O)(=O)CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonylmethanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 416. NMR (CDCl3): 2.67-2.70 (4H, m), 3.24 (3H, s), 3.49-3.54 (4H, m), 3.90 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 4.42 (2H, s), 5.24 br s), 7.30 (1H, s), 9.30 (2H, s). MS (ESI+): MH+ 569.17 (100%)
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:14]1([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]([NH2:29])=O)=[CH:19]2)[CH2:16][CH2:15]1>O1CCOCC1.C(N(CC)CC)C.ClCCl>[CH:14]1([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]#[N:29])=[CH:19]2)[CH2:15][CH2:16]1
Reactant: NC(=O)c1cn(CC2CC2)c2ccccc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cn(CC2CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic anhydride (19.5 g) was added dropwise to a cooled (0° C.), stirred solution of 1-cyclopropylmethyl-1H-indole-3-carboxamide (5 g) in dioxane (100 ml) and triethylamine (18 g). After the addition the mixture was stirred at room temperature for two hours, the mixture was diluted with dichloromethane (200 ml) and washed with water (3×100 ml), dried (Na2SO4) and evaporated at reduced pressure. The residue was purified by column chromatography on silica eluting with dichloromethane to afford a colourless oil, (5 g); δH (CDCl3, 60 MHz) 0.3-0.6 (4H, m, 2×CH2), 0.9 (1H, m, CH), 4.0 (2H, d, J=7, CH2), 7.0-7.7 (5H, m); νmax 2210 (C≡N).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12](=[S:15])([O-:14])[CH3:13].[K+]>C(O)C>[C:12]([S:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 3-(bromomethyl)benzoic acid (7 g, 32.56 mmol, 1.00 equiv) in ethanol (80 mL), and potassium ethanethioate (9.65 g, 84.65 mmol, 2.60 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 80 mL of water and adjusted to pH 3-4 with 10% hydrochloric acid. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, washed with 1×50 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 4.4 g (64%) of 3-(acetylthiomethyl)benzoic acid as a brown solid.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19](=[O:26])[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:16]=2)[N:11]([CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=2[O:38][CH3:39])[N:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH:21]1([CH2:20][C:19]([NH:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([OH:8])=[N:10][N:11]3[CH2:27][C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=3[O:38][CH3:39])=[CH:16][CH:15]=2)=[O:26])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc(Cn2nc(OCc3ccccc3)c3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2nc(O)c3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Yield: 61.7 %

Procedure:
A mixture of methyl 4-[3-benzyloxy-6-(2-cyclopentylacetamido)indazol-1-ylmethyl]-3-methoxybenzoate (BB) (5.0 g.), and palladium-on-carbon (5% w/w, 1.25 g.), in ethyl acetate (190 ml.), was hydrogenated at 1.1 bar for 7.5 hours. The catalyst was removed by filtration through diatomaceous earth, washing the filter cake with ethanol, the filtrate partially evaporated, and the residue allowed to crystallize to give the title compound (2.56 g., 62%), as a solid, m.p. 242°-245° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([OH:35])=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C(O)=O)=CC=5)C=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[NH2:99][CH2:100][CH2:101][N:102]1[CH2:107][CH2:106][O:105][CH2:104][CH2:103]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([NH:99][CH2:100][CH2:101][N:102]5[CH2:107][CH2:106][O:105][CH2:104][CH2:103]5)=[O:35])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Reactant: NCCN1CCOCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)NCCN4CCOCC4)c3)cn2)cc1
Yield: 99.9 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (69.6 mg, 0.105 mmol) obtained in Step A in Example 1-D-53 instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and N-(2-aminoethyl)morpholine (27.5 mg, 0.211 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide as a yellow solid (81.0 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-123) as a yellow powder (34.2 mg, 60%).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[BH4-].[Na+].Cl>CO.CCOC(C)=O>[C:2]12([OH:1])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[OH:12])[CH2:3]1)[CH2:9]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC1C2CC3CC1CC(O)(C3)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A stirred solution of 1-hydroxy-4-adamantanone (10.53 g, 63.4 mmol) in MeOH (100 mL) was cooled in an ice bath and NaBH4 (5×1-g caplets, 5.0 g, 130 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight. 5% aq HCl (25 mL) was added and the mixture was concentrated to leave a white solid. This material was suspended in EtOAc (350 mL) and 5% aq HCl (100 mL) and filtered. The organic layer of the filtrate was collected, washed with brine, dried over Na2SO4 and concentrated to afford 1,4-adamantanediol (4.47 g, 41%).