Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2cccc(O)c2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of 6-bromo-4-(3-methoxy-phenyl)-2-methoxy-quinoline (1.31 g, 3.81 mmol) in dichloromethane (CH2Cl2, 30 ml) was added a solution of BBr3 in CH2Cl2 (1M, 11.4 ml, 11.4 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. It was poured into water. The organic layer was washed with brine, dried over MgSO4 and concentratred to give the title compound of example 34A (640 mg, 41% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC#N>[C:1]([C:5]1[C:9]([F:28])=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)c(F)c1Nc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in CH3CN (1 mL) was added [(1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (SELECTFLUOR™) (48 mg, 0.14 mmol), and the mixture was stirred at rt for 16 h. The mixture was concentrated, and the residue was subjected to HPLC purification with a gradient elution from 10% to 90% acetonitrile in water to afford 22 mg (42%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.18 (s, 1H), 8.04 (d, 1H), 7.50 (dd, 1H), 7.42 (m, 1H), 7.28 (m, 1H), 7.13 (m, 2H), 2.12 (s, 6H), 1.40 (s, 9H). ES-MS m/z 383.1 (MH+); HPLC RT (min) 3.21.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (10.5 g., 0.075 mole) in ethanol (30 ml.) is added to a solution of levo-4-(2-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (14.67 g., 0.045 mole) and sodium hydroxide (2.40 g., 0.06 mole) in water (150 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (30 ml.), and the solid (yellow) which forms after scratching is filtered and air-dried to yield 24.1 g. of material with m.p. 150°-165°C. (sinters at 140°). Several recrystallizations from n-butyl chloride, followed by several recrystallizations from acetonitrile gives a white solid, m.p. 189°-190°C., [α]D25 = -61.5 (in 1% CHCl3).
Reaction SMILES: FC1C=C(NC2N=C3NN=CC3=C([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:27]=[CH:28][CH:29]=3)N=2)C=CC=1N1CCOCC1.ClC1N=C(Cl)N=C2NN=CC=12.O1C=CCCC1.Cl[C:53]1[N:58]=[C:57]([Cl:59])[N:56]=[C:55]2[N:60]([CH:63]3[CH2:68][CH2:67][CH2:66][CH2:65][O:64]3)[N:61]=[CH:62][C:54]=12.C(NC1C=C(B(O)O)C=CC=1)(=O)C=C>>[Cl:59][C:57]1[N:56]=[C:55]2[N:60]([CH:63]3[CH2:68][CH2:67][CH2:66][CH2:65][O:64]3)[N:61]=[CH:62][C:54]2=[C:53]([C:28]2[CH:27]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:25]=[CH:24][CH:29]=2)[N:58]=1
Reactant: Clc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(F)c3)nc3[nH]ncc23)c1
Agent: C1=COCCC1
Agent: C=CC(=O)Nc1cccc(B(O)O)c1
Agent: Clc1nc(Cl)c2cn[nH]c2n1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1

Procedure:
As an example, N-(3-(6-((3-fluoro-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide can be prepared according to Route II. Beginning with 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, protection can be accomplished by reaction with 3,4-dihydro-2H-pyran. The resulting 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine can then be coupled with (3-acrylamidophenyl)boronic acid under palladium catalyzed conditions to provide N-(3-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)Cl.[O-]Cl.[Na+].[C:16](=S)=[S:17]>O>[CH2:1]([N:7]=[C:16]=[S:17])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: S=C=S
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: S=C=NCc1ccco1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Furfurylamine (9.71 g) is added over 30 minutes to a stirred, cooled mixture of 8.84 g of NaOH, 20 ml of CH2Cl2, 15 ml of H2O and 7.5 ml of CS2. The mixture is stirred 55 minutes in the ice bath and 600 ml of 5.25% aqueous NaOCl solution is added over 1 hour and 45 minutes (temperature is maintained at 8° C. or less). After stirring 16 hours at 20° C., the reaction mixture is extracted three times with CH2Cl2 (total volume of combined CH2Cl2 extracts is 600 ml). The CH2Cl2 extract is washed with 2×100 ml of H2O, dried with Na2SO4 and evaporated to give 12.4 g of crude furfurylisothiocyanate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[CH3:38][C@@H:39]1[CH2:41][O:40]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:40][C@H:39]([CH3:41])[CH2:38][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Reactant: C[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OC[C@@H](C)O
Yield: 24.4 %

Procedure:
The title compound was prepared according to the procedure described in Example 15 by using N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (5.5 g, 11.1 mmol), (R)-2-methyloxirane (8 ml, 111 mmol) and K2CO3 (3.1 g, 222.2 mmol) in DMF/H2O (25 mL/5 mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH(V/V=40/1)) to afford the title compound as a gray-white solid (1.5 g, 25%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[C]=[O:7].C=O.[O:10]1[CH2:14][CH2:13]CC1>>[C:3]([N:2]([CH2:13][C:14]([OH:10])=[O:7])[CH3:1])(=[O:5])[CH3:4]
Reactant: CNC(C)=O
Reactant: C1CCOC1
Reactant: [C]=O
Agent: C=O
Product: CC(=O)N(C)CC(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A 1 L autoclave was charged with N-methylacetamide (IX) (90 g, 1.23 mole), Co(OAc)2.4H2O (16.5 g, 0.13 mole), and tetrahydrofuran (500 mL). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H2 (70:30) was established at 25° C. with stirring at 2000 rpm. The contents of the autoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H2 (70:30) was established. After approximately one hour, rapid gas uptake was observed. The reaction mass was cooled to 65° C. and the pressure was slowly reduced to 1500 psi (10,345 kPa). At this point carbon monoxide was established as the carboxymethylation feed gas. Under a constant 1500 psi (10,345 kPa), 47 Wt. % formalin (180 mL, 2.97 mole) was delivered at 6 mL/min. The reaction was stirred at 65° C. for 30 min. after the formalin addition was complete. Then the reaction was cooled to 25° C., removed from the autoclave, and assayed for N-acetylsarcosine (XX). This resulted in an 85% yield of (XX).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].O>CN(C=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]=1[C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of 4-chloro-2-(ethoxycarbonylamino)benzonitrile (10.8 g) in DMF (50 ml) cooled to 0° C. was added sodium hydride (60% w/w dispersion in mineral oil, 2.0 g, 50 mmol). The mixture was stirred for 30 min at 0° C. and then 2-bromoacetophenone (9.9 g, 50 mmol) was carefully added. After stirring for an additional 15 h at 0° C., the mixture was poured into water (500 ml) and extracted with diethyl ether (500 ml×2). After drying (MgSO4) and removal of solvent, the crude product was purified by flash chromatography eluting with ethyl acetate/hexane (1:5) to afford 11.8 g (72%) of the title compound as a brown amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:35][CH2:36][C:37](Cl)=[O:38]>C(Cl)Cl>[Br:35][CH2:36][C:37]([NH:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1)=[O:38]
Reactant: O=C(Cl)CBr
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CBr)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of (2R)-2-[(4-aminobenzyl)-(4-chloro-benzenesulfonyl)amino]-4-methyl-pentanoic acid amide (248 mg, 0.56 mmol) and Et3N (176 mg, 1.74 mmol) in CH2Cl2 (3 mL) was added bromoacetylchloride (105 mg, 0.67 mmol). The reaction mixture was stirred overnight at rt. The reaction mixture was diluted with CH2Cl2 (5 mL), washed with 1 N HCl, brine, and dried through a cotton plug. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% acetone/CH2Cl2) afforded the title compound (124 mg) in 42% yield. MS (ESI), (M+H)+531.86, 1H NMR (CDCl3, 400 MHz) δ8.78 (br s, NH), 7.95 (d, 2H, J=8.0), 7.82 (d, 2H, J=8.0), 7.42 (d, 2H, J=8.0), 7.33 (d, 2H, J=8.0), 6.20 (br s, 1H), 5.20 (br s, 1H), 4.30 (s, 2H), 4.22 (d, 1H, Jab=16), 4.14 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH:21]=2)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([C@@H:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]2=[O:31])=[CH:21]1
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC[C@@H](CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Reaction time: 12 h

Procedure:
To a solution of (S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (4.2 g, 9.8 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was added LiOH (234 mg, 9.8 mmol) at room temperature. The solution was stirred at the same temperature for 12 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that precipitated out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product (S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid (3.7 g, 92%). LC-MS (M++1): 406.27.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([OH:12])=O)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].Cl.[CH2:15]([O:18][C:19]1[C:28]([CH3:29])=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][C:20]=1[CH3:30])[CH:16]=[CH2:17].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)C>[CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:21]=[C:20]([CH3:30])[C:19]([O:18][CH2:15][CH:16]=[CH2:17])=[C:28]([CH3:29])[CH:27]=2)=[O:12])[S:8][CH:9]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1c(CC(C)C)csc1C(=O)O
Reactant: C=CCOc1c(C)cc(C(=O)NN)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOc1c(C)cc(C(=O)NNC(=O)c2scc(CC(C)C)c2C)cc1C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
A solution of 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (100 mg, 0.5 mmol), 4-allyloxy-3,5-dimethyl-benzoic acid hydrazide hydrochloride (192 mg, 0.75 mmol) and NEt3 (0.28 mL) in DMF (10 mL) is cooled at 0° C. and TBTU (200 mg, 0.6 mmol) is added. The mixture is stirred for 15 h while warming from 0° C. to rt. The mixture is diluted with diethyl ether (50 mL) and washed with 1M aq. NaOH (2×20 mL), 1M aq. HCl (2×20 mL) and brine (10 mL). The organic phase is dried (Na2SO4), filtered and evaporated to give 160 mg of 4-allyloxy-3,5-dimethyl-benzoic acid N′-(4-isobutyl-3-methyl-thiophene-2-carbonyl)-hydrazide; LC-MS: tR=1.05 min, [M+1]+=400.83.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29](OC(C)(C)C)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:44][O:45][C@@H:46]([C@@H:64]1[CH2:68][CH2:67][CH2:66][NH:65]1)[C@@H:47]([CH3:63])[C:48]([NH:50][C@H:51]([C:59]([O:61][CH3:62])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:49].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([N:65]3[CH2:66][CH2:67][CH2:68][C@H:64]3[C@H:46]([O:45][CH3:44])[C@@H:47]([CH3:63])[C:48]([NH:50][C@H:51]([C:59]([O:61][CH3:62])=[O:60])[CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:49])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a stirring mixture of dimer acid #5 (12.1 g, 23.0 mM) and #67 (11.5 g, 23.0 mM) in 75 mL of dichloromethane under nitrogen, HATU (10.8 g, 27.6 mM) was added followed by Hunig's base (12.1 mL, 69.0 mM). The reaction was allowed to stir at room temperature for 15 hours. Reaction was concentrated to a smaller volume, taken up with ethyl acetate and washed with 1 N HCl two times. The organic layer was then washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Residue was then purified by silica gel chromatography (Gradient: 0% to 70% acetone in heptanes), producing #113 (12.3 g, 62%) as a white solid. LC-MS (Protocol Q): m/z 855.3 [M+H+], 877.2 [M+Na+], retention time=2.32 minutes; HPLC (Protocol R): /z 855.5 [M+H+], retention time=9.596 minutes (purity >97%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[N:3]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:22])=[O:12])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc2c(C=O)c(Cl)n(-c3ccccc3)c2c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc2c(C(=O)O)c(Cl)n(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.8 %

Procedure:
The compound of step 2 (365 mg, 1.27 mmol) was dissolved in tert-butanol (15 ml) and 2-methyl-2-butene (3 ml), and a solution of sodium chlorite (1.06 g, 11.7 mmol) and sodium dihydrogenphosphate (1.06 g, 8.82 mmol) in water (6 ml) was added. The reaction mixture was stirred at room temperature for 48 h. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give 394 mg of the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH:20](C(O)=O)[CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH3:24])[C:10]=3[CH2:9]2)=O)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]([C:31]#[C:32][C:33]([O:35][CH3:36])=[O:34])=[O:30]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[N:8]3[C:20]([CH2:19][C:18]4[C:17]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[N:11]([CH3:24])[C:10]=4[CH2:9]3)=[C:31]([C:29]([O:28][CH3:27])=[O:30])[C:32]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccccc31)CC(C(=O)O)N(C(=O)c1ccc(Cl)cc1)C2
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)cc2)n2c1Cc1c(n(C)c3ccccc13)C2
Temperature: 80 °C

Procedure:
A mixture of 2-(4-chlorobenzoyl)-9-methyl-1,2,3,4-tetra-hydropyrido[3,4-b]indole-3-carboxylic acid (4 g, 10.8 mmol), DMAD (2.3 g, 16.3 mmol) in AC20 (30 mL) was heated at 80° C. for 2 h. The reaction mixture evaporated in vacuo to dryness. The residue was recrystallized from MeOH to give dimethyl 3-(4-chlorophenyl)-6-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate, 3.5 g, (72%); mp 264-265° C. 1H NMR (DMSO-d6) δ 3.60 (6H, s, 2×COOMe), 3.78 (3H, s, NMe), 4.30 (2H, s, CH2), 5.18 (2H, s, CH2), 7.06-7.10 (1H, m, ArH), 7.17-7.20 (1H, m, ArH), 7.45-7.47 (1H, m, ArH), 7.54-7.59 (5H, m, 5×ArH). Anal. Calcd for (C25H21ClN2O4): C, 66.89; H, 4.72; N, 6.24. Found: C, 66.82; H, 4.63; N, 6.24.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].CO.O.[OH-].[Li+]>C1COCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CNc1ccc(C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NCC(=O)O)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a solution of the product of step 1 (1.1 gm, 5.3 mmoles) in a mixture of THF (12 ml), methanol (4 ml) and water (4 ml), lithium hydroxide (444 mg, 10.6 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water, acidified with 1N HCl and evaporated in vacuum. The residue was diluted with ethyl acetate, stirred for 30 min and filtered. The filtrate was concentrated in vacuum to yield 1.0 gm (98%) of title product as off white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([O:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCOCC>[CH3:22][C:16]1[CH:15]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:21][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([O:13][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cc1c(Cl)ncnc1OC
Reactant: Cc1cccc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C)c1

Procedure:
A mixture of methyl 4-chloro-6-methoxy-pyrimidin-5-yl-acetate (21.7 g, 100 mmol), m-cresol (10.8 g, 100 mmol), potassium carbonate (20.7 g, 150 mmol) and a catalytic amount of 18-crown-6 in dimethylformamide (50 ml) is heated to +120° C. for 1 hour. Addition of crushed ice, extraction with ether and drying gives the methyl 4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl-acetate as an oil.
Reaction SMILES: [BH3-][C:2]#[N:3].[Na+].[C:5]([NH:15][C@H:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:29]=O>CO.[Cl-].[Cl-].[Zn+2]>[CH3:29][N:3]([CH3:2])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:15][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Product: CN(C)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A mixture consisting of 3.7 (27.2 mmol) of ZnCl2, 3.2 g (53 mmol) of NaCNBH3 and 60 mL of methanol was prepared to which was added a solution of 18 g (51.7 mmol) of the amine 1 in 180 mL of methanol. After cooling to 10°-15° C. 12.4 mL of 37% formaldehyde (165 mmol) was added dropwise over a 2-3 minute period. The reaction was stirred for 1 hour and monitored by silica gel TLC with elution using a 60:10:1(v/v/v/) mixture of chloroform/methanol/concentrated ammonia (solvent A). One hundred milliliters of water was added and the mixture concentrated to a volume of 200 ml. Ethyl acetate (200 mL) was added and the pH raised to 10.5 with 10% NaOH. The ethyl acetate was separated and the pH of the aqueous phase readjusted to 10.5 and extracted with 200 mL of fresh ethyl acetate. The ethyl acetate extracts were combined, washed with NaCl, dried over Na2SO4, filtered and concentrated to yield, after drying overnight under high vacuum, 14.86 g of viscous oil.