Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N[C:3]1[C:8]([Br:9])=[CH:7][C:6]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]([CH3:16])=[N:14][CH:15]=2)=[CH:5][C:4]=1[Br:22].N([O-])=O.[Na+].[PH2](O)=O>C(O)(=O)C.O.C(N(CC)CC)C>[Br:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]([CH3:16])=[N:14][CH:15]=2)[CH:5]=[C:4]([Br:22])[CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cc(Br)c(N)c(Br)c2)cnc1C
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2cc(Br)cc(Br)c2)cnc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
Hydrochloric acid (11.5N, 0.90 ml) was added to 5-(4-amino-3,5-dibromophenyl)-3-ethoxycarbonyl-2-methyl pyridine (2 g) in glacial acetic acid (20 ml). Sodium nitrite (0.37 g) in water (2 ml) was added at 0°-5° C. and, after standing for 0.5 hour at this temperature, the mixture was poured into 30% aqueous hypophosphorous acid (3.88 g) in water (10 ml). The mixture was stirred at room temperature for 0.5 hour, diluted with water, made alkaline with triethylamine and extracted with diethyl ether. The extract was washed with sodium bicarbonate solution and water, dried and filtered through a column of silica. Concentration of the filtrate and recrystallisation of the residue from petroleum ether (b.p. 40°-60°) gave the title compound (0.97 g), m.p. 100°-2°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[OH:21][C@@H:22]([CH3:40])[CH2:23][N:24]1[CH2:29][CH:28]=[C:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([O:38][CH3:39])[CH:31]=2)[CH2:26][CH2:25]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([C:27]4[CH2:28][CH2:29][N:24]([CH2:23][C@@H:22]([OH:21])[CH3:40])[CH2:25][CH:26]=4)=[CH:31][C:32]=3[O:38][CH3:39])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(C2=CCN(C[C@H](C)O)CC2)ccc1C=O
Product: COc1cc(C2=CCN(C[C@H](C)O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 44 %

Procedure:
In a similar fashion as for the synthesis of III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4[1-((S)-2-hydroxypropyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2-methoxybenzaldehyde were reacted to produce the title compound (44%). 1H NMR (d-4 methanol): 8.26 (d, J=7 Hz, 1H), 7.94 (s, 1H), 7.24 (m, 2H), 6.42 (m, 2H), 6.31 (s, 1H), 5.33 (m, 1H), 4.29 (m, 1H), 4.11 (s, 3H), 4.07 (m, 2H), 3.65 (m, 2H), 3.39-3.27 (m, 6H), 3.17 (m, 1H), 3.07-2.85 (m, 4H), 2.77 (d, J=7 Hz, 1H), 2.34 (d, J=7 Hz, 1H), 1.57 (d, J=7 Hz, 1H), 1.56 (d, J=7 Hz, 1H), 1.30 (d, J=7 Hz, 3H). MS: 549.19 (M+H). HPLC retention time: 1.86 minutes (G Method).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[F:19][C:20]([F:34])([F:33])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)[NH2:22].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:13])[NH:22][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[C:20]([F:34])([F:33])[F:19])[NH:8]2)=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 26.6 %

Procedure:
A solution of the crude product of 6-chloro-5-(ethoxycarbonyl)-1H-indole-2-carboxylic acid (1.9 g) from Synthesis Example 1, Stage 2 and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (1.12 g, 4.60 mmol) (lit. DE 2723464) in N,N-dimethylformamide (15 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (953 mg, 4.60 mmol), and the mixture was stirred at room temperature for 4 days. The reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat. sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 25% ethyl acetate) gave 603 mg (26% of theory over 2 stages) of ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CC1C(C)=N[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([NH2:46])[CH:41]=2)N=1>>[CH2:2]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([NH:46][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:41]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Cc1nc2ccc(N)cc2nc1C
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo-[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 2,3-dimethyl-6-quinoxalinamine by a procedure similar to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.66 (s, 6H), 6.66 (d, 1H, J=5.4 Hz), 7.19 (t, 1H, J=6.9 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.43 (d, 1H, J=7.7 Hz), 7.51-7.65 (m, 3H), 7.85-7.88 (m, 2H), 7.99-8.03 (dd, 1H, J=2.3, 9.0 Hz), 8.06 (s, 1H), 8.42 (d, 1H, J=5.3 Hz), 8.60-8.64 (m, 2H), 8.91 (d, 1H, J=6.9 Hz), 10.08 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=558.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:29][O:30][CH3:31])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:12]=1)C1C=CC=CC=1>Cl>[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]([N:27]([CH2:28][CH2:29][O:30][CH3:31])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:14]=[CH:15][CH:16]=1
Reactant: COCCN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)c1cccc(NC(=O)OCc2ccccc2)c1
Agent: Cl
Product: COCCN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{3-[1-[tert-Butoxycarbonyl-(2-methoxy-ethyl)-amino]-2-(tert-butyl-dimethyl-silanyloxy)ethyl]-phenyl}-carbamic acid benzyl ester was added to ethanolic HCl (20 mL) at 0° C., allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated to give the title compound as a light yellow oil (300 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:33]([C:21]1([C:24]([O:26][CH3:27])=[O:25])[CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19][CH2:20]1)[CH2:32][CH2:31][CH:30]=[CH2:29]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of potassium bis(trimethylsilyl)amide (30.7 g, 0.15 mol) in tetrahydrofuran (750 mL) at 0° C. was added a solution of methyl 1-(tert-butoxycarbonyl)piperidine-4-carboxylate (25 g, 0.10 mol) from Step A in tetrahydrofuran (250 mL) and the reaction mixture was stirred for 1 h. 5-Bromo-1-pentene (19.4 mL, 0.164 mol) was added and the reaction mixture was allowed to warm to room temperature for 1.5 h. The reaction mixture was then poured into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound (30.9 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH2:11][CH2:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])(=[O:3])N.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[O:18]=[C:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[CH2:10][CH2:11][N:12]2[CH:13]=[C:4]([C:1]([OH:20])=[O:3])[CH:5]=[C:6]12
Reactant: NC(=O)c1cc2n(c1)CCc1ccccc1C2=O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2n(c1)CCc1ccccc1C2=O
Yield: 89 %

Procedure:
To 2-carbamoyl-6,11-dihydro-pyrrolo[2,1-b][3]benzazepine-11-one (27 g., 0.112 moles) in 300 ml. of 50% sulfuric acid maintained over 50° C., was added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid was filtered, washed with water and air-dried to yield 6,11-dihydro-11-oxo-pyrrolo[2,1-b][3]benzazepine-2-carboxylic acid (24 g., 89%), m.p. 287°-290° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.Cl.C(O)=[O:12]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:12])[CH:5]=[CH:4][N:3]=1
Reactant: O=CO
Reactant: N#Cc1ccnc(Cl)n1
Agent: Cl
Product: NC(=O)c1ccnc(Cl)n1
Reaction time: 8 h

Procedure:
338 g of 98% strength formic acid are introduced into a 1--1 round bottom flask fitted with magnetic stirring and containing 131.9 g (946 mmol) of 2-chloropyrimidine-4-carbonitrile, and a stream of gaseous hydrochloric acid is passed through slowly for 1 h 30 min. The mixture is allowed to stand overnight, the solid is isolated on sintered glass and is then purified by recrystallisation with filtration while hot, from a mixture of nitromethane and ethyl acetate. In this way, 107.03 g of grey solid are isolated as three crops, after drying under vacuum and with heating. Melting point: 152.5°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[N:13][C:14]2[N:15]([C:17]([C:20]3([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:22][CH2:21]3)=[CH:18][N:19]=2)[CH:16]=1)[C:5]([OH:7])=O.CN.F[P-](F)(F)(F)(F)F.[N:42]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:46]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[N:13][C:14]2[N:15]([C:17]([C:20]3([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:22][CH2:21]3)=[CH:18][N:19]=2)[CH:16]=1)[C:5]([NH:42][CH3:46])=[O:7]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Fluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoic acid obtained from Step 2 was dissolved in N,N-dimethylformamide (1 mL). To this solution was added methylamine (2M in THF, 0.2 mL), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.68 mmol). The solution was stirred overnight at RT, diluted with MeOH, and purified by RP-HPLC (pH 10) to afford the desired compound. LCMS (M+H): m/z=438.0.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:27][C:26]2[C:18]([F:17])=[C:19]([C:23]([F:28])=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2nc(CBr)sc2Br)cc1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
To a solution of 5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)-thiazole (0.50 g, 1.37 mmol) in 5 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.23 g, 1.37 mmol) and potassium carbonate (0.75 g, 5.43 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (30:70) as the eluent to provide the title compound (0.30 g, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([NH:10][CH2:11][CH:12](OC)OC)[CH2:8][O:9][C:4]=2[C:3]=1[C:19]([O:21][CH3:22])=[O:20]>Cl.CO>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[CH:12]=[CH:11][N:10]=[C:7]3[CH2:8][O:9][C:4]=2[C:3]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1c(N)ccc2c1OCC(NCC(OC)OC)=N2
Agent: Cl
Solvent: CO
Product: COC(=O)c1c(N)ccc2c1OCc1nccn1-2
Yield: 53.1 %

Procedure:
A solution of methyl 7-amino-3-(2,2-dimethoxyethylamino)-2H-benzo[1,4]oxazine-8-carboxylate (Intermediate 27, 0.910 g) in concentrated aqueous hydrochloric acid (8 mL) and methanol (10 mL) was heated to reflux for 3 hours. After cooling, the mixture was concentrated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water and basified with 2M aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 50-100% and then a mixture of methanol and ethyl acetate (5%) to give methyl 7-amino-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate (0.383 g) as a sandy coloured solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
30 mg (0.09 mmol) of the compound of Example 46A is reacted analogously to the synthesis of the compound of Example 4 with 9 mg (0.09 mmol) of 2-oxopiperazine. 42 mg (89% of theory) of the title compound is obtained.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:8][C:7]2[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH:1]=[O:13])=[CH:3][C:4]=2[O:5][CH3:6])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccc(C(C)C)cc1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
Syringaldehyde (4-hydroxy-3,5-dimethoxybenzaldehyde) (10.2 g, 55 mmol) was dissolved in DMF (45 ml), and 4-isopropylbenzylchloride (9.7 g, 55 mmol) and potassium carbonate (11.5 g) were added successively. The resulting mixture was heated at 60° C. for 16 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (3×100 ml). The combined organic extracts were washed with water (100 ml), saturated NaCl (100 ml), dried (MgSO4), treated with activated carbon, filtered and concentrated in vacuo to afford 15 g (100%) of 4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21](Cl)=[N:20][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[N:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1>>[O:29]1[CH2:30][CH2:31][N:26]([C:23]2[C:24]3[S:25][C:17]([CH2:16][N:13]4[CH2:14][CH2:15][N:10]([S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])[CH2:11][CH2:12]4)=[CH:18][C:19]=3[N:20]=[C:21]([C:37]3[CH:36]=[N:35][C:34]([NH2:33])=[N:39][CH:38]=3)[N:22]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccccc5)CC4)cc3n2)cn1

Procedure:
6-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 120. (400 MHz, CDCl3): 2.56-2.58 (4H, m, CH2), 3.04 (4H, m, CH2), 3.74 (2H, s, CH2), 3.76-3.79 (4H, m, CH2), 3.90-3.92 (4H, m, CH2), 7.18 (1H, s, ar), 7.47-7.51 (1H, d (J=7.36), ar), 7.55 (1H, d (J=7.36), ar), 7.71 (2H, d (J=7.07), ar), 9.19 (2H, s, ar). (M+H)+ 553.29
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([NH:22][C@H:23]([CH2:26][CH3:27])[CH2:24]O)(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[NH2:22][C@H:23]([CH2:26][CH3:27])[CH2:24][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (3.00 g, 13.3 mmol) was reacted with N-Boc-(R)-(+)-2-amino-1-butanol (2.76 g, 14.6 mmol) in the presence of triphenylphosphine and DIAD using the method of Example 99. After Boc-deprotection 1.48 g (41%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ. 0.87-0.94 (m, 3H), 1.11-1.40 (m, 2H), 2.97-3.06 (m, 1H), 4.01 (dd, 1H), 4.13 (dd, 1H), 4.68-4.84 (m, 1H), 6.96 (d, 1H), 7.86 (d, 1H), 7.94 (dd, 1H), 7.97 (dd, 1H), 8.09-8.11 (m, 1H). MS [M+1]: m/z [274.8+1].
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[NH:4][C:3]1=S.[BH4-].[Na+]>CO.C1COCC1.[Ni]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:1])[CH2:3][NH:4]2
Reactant: CCOC(=O)CC1(C)C(=S)Nc2cccc([N+](=O)[O-])c21
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC1(C)CNc2cccc(N)c21
Reaction time: 1 h

Procedure:
To a solution of (±)-ethyl (3-methyl-4-nitro-2-thioxo-2,3-dihydro-1H-indol-3-yl)acetate from Step A (3.65 g, 12.4 mmol) and nickel (H) chloride hexahydrate (23.6 g, 99.2 mmol) in MeOH (30 mL) and THF (30 mL), at 0° C., was added NaBH4 (11.3 g, 298 mmol) in portions, over 1 h. The resulting mixture was stirred for 10 min, then filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—90:10, to give the title compound. MS: m/z=235 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=C[CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].[N:29]1C=CC=C(OCC2CCCN2S(C2C=C3C(=CC=2)NC(=O)C3=O)(=O)=O)C=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:19][O:20][C:21]3[CH:26]=[N:29][CH:24]=[CH:23][CH:22]=3)(=[O:12])=[O:13])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28]
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc2C1=O
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCCC3COc3cccnc3)ccc21
Yield: 55 %

Procedure:
1-Methyl-5-(2-(pyridin-3-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (21a) was prepared according to the same procedure for compound 11a, except using compound 20, and the crude product was purified with ethyl acetate to afford 55 mg (55%) of 21a as a yellow solid, mp 142.1-143.4° C. 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=2.7, 1H), 8.22 (dd, J=3.9 Hz, J=2.1 Hz, 1H), 8.08 (dd, J=8.4, J=2.1 Hz, 1H), 7.26 (s, 1H), 7.21 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 4.22 (m, 1H), 3.98 (m, 2H), 3.53 (m, 1H), 3.30 (s, 3H), 3.22 (m, 2H), 2.03 (m, 2H), 1.80 (m, 2H). LCMS m/e: 401.84 (M+H). Anal. Calcd for C19H19N3O5S: C, 56.85, H, 4.77; N, 10.47. Found: C, 56.48, H, 4.87; N, 10.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12]4[C:17]([CH2:18][C:6]=3[C:5]=2[CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C@@H:7]3[C:12]4[C:17]([CH2:18][C@@H:6]3[C:5]=2[CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: COc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5,10-Dihydro-8-methoxyindeno[1,2-b]indole (770 mg, 3.3 mmol) was reacted with sodium cyanoborohydride (1.0 g, 16 mmol), in glacial acetic acid (17 cm3) solution. After 30 minutes, the solution was poured into ice/water, stirred for 1 hour, and neutralised with sodium hydroxide. The colourless reaction mixture was extracted into diethylether, the organic layers, dried (Na2SO4), and concentrated in vacuo. The residue was column chromatographed (10% ethyl acetate/petrol 60°-80° C.) to yield the title compound as a colourless solid. Yield: 520 mg (66%). M.p. 101° C. 1H NMR (CDCl3) δ: 3.28 (1H, dd,), 3.57 (1H, dd,), 3.80 (3H, s,), 3.85 (1H, br,), 4.24 (1H, dd,), 5.30 (1H, d,), 6.6-7.4 (7H, m,).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.C(#N)C.CCN(C(C)C)C(C)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:3]2[N:4]([CH:9]=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1cn2nc(Cl)cc(Br)c2n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)Cc1cn2nc(Cl)cc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 28a (1.80 g, 5.66 mmol) was placed in a 20 mL vial equipped with a stir bar and then ACN (11 mL) was added. Once the mixture was homogeneous, DIEA (1.79 mL, 10.3 mmol) was added. Morpholine (0.601 mL, 6.90 mmol) was added and then the reaction was stirred at rt for 3 h during which time the entire solution solidified. The solid was broken up and additional ACN (2 mL) was added. The reaction was stirred for an additional 2 h at rt. The reaction was poured into water (50 mL) and the resulting precipitate was isolated by filtration. The solid was washed with water (2×20 mL) and then dried under reduced pressure to afford compound 28b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.73 (s, 1H), 6.05 (s, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.97-4.05 (m, 4H), 3.86-3.93 (m, 4H), 3.79 (s, 2H), 1.28 (t, J=7.2 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C14H17ClN4O3: 325.1 (M+H). Found: 325.1.