Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[N:11]([C:12]4[C@H:13]5[CH2:22][C@@H:16]([C:17]=4[CH:18]=3)[CH2:15][CH2:14]5)[CH2:10][CH2:9]2)[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][C@@H:49]3[CH3:58])=[CH:44][N:43]=2)[C:27]1=[O:59].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:25][N:26]1[C:27](=[O:59])[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:55][O:56][CH2:57]4)[CH2:50][C@@H:49]3[CH3:58])=[CH:44][N:43]=2)=[CH:29][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[N:11]([C:12]5[C@H:13]6[CH2:22][C@@H:16]([C:17]=5[CH:18]=4)[CH2:15][CH2:14]6)[CH2:10][CH2:9]3)[C:3]=2[CH:23]=[O:24])=[CH:31]1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2[C@@H]2CC[C@H]3C2)C1=O
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5[C@@H]5CC[C@H]6C5)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 43.6 %

Procedure:
A round-bottomed flask was charged with 4-chloro-2-[(1R,11S)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehyde 170b (200 mg, 0.59 mmol), 1-methyl-3-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 191j (400 mg, 0.88 mmol), PdCl2(dppf) (50 mg, 0.06 mmol), K3PO43 water (300 mg, 1.20 mmol), sodium acetate (100 mg, 1.20 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 174a as a red solid (170 mg, 44%). MS-ESI: [M+H]+ 661.3
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[N:41]([CH3:50])[C:42]([C:45]([CH3:49])([CH3:48])[CH:46]=O)=[N:43][N:44]=1>C1COCC1>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[N:41]([CH3:50])[C:42]([C:45]([CH3:49])([CH3:48])/[CH:46]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:43][N:44]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
Benzyltriphenylphosphonium bromide (1.15 g) was suspended in THF (30 ml) and, under ice cooling, n-butyllithium (1.60M hexane solution, 1.50 ml) was added thereto, followed by stirring at room temperature for 30 minutes. A THF (20 ml) solution of 2-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-2-methylpropanal (633 mg) was added dropwise to the reaction solution and the whole was stirred under heating and refluxing for 20 hours. The reaction mixture was quenched with water (50 ml) and then extracted with ethyl acetate (50 ml×2). The organic layer washed with a 1M aqueous hydrochloric acid solution (30 ml), a saturated aqueous sodium bicarbonate solution, and a brine (30 ml). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98) and preparative thin layer chromatography (ethyl acetate:hexane=3:1) to obtain 86 mg of 3-(2-chlorophenyl)-5-[(2E)-1,1-dimethyl-3-phenylprop-2-en-1-yl]-4-methyl-1,2,4-triazol (white solid).
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23]1>C(O)(=O)C>[Br:1][C:26]1[O:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=1
Reactant: [Br-]
Reactant: O=C(O)c1ccoc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(O)c1coc(Br)c1
Temperature: 40 °C

Procedure:
To a stirred solution of pyridinium tribromide (14.3 g, 44.6 mmoles) in acetic acid (20 ml) was added 3-furoic acid (5 g, 44.6 mmoles). The resulting mixture was heated at 40° C. for 16 hours. The acetic acid was evaporated; the residue was dissolved in dichloromethane (50 ml), washed with water (3×50 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC (gradient: 20% acetonitrile/80% water containing 0.1% trifluoroacetic acid to 80% acetonitrile/20% water at a rate of 1%/min) to afford 5-Bromo-furan-3-carboxylic acid (7) as a white solid. LC/MS System A; Rt=2.52 mins, m/z (ES−)=189/191 (M−H for C5H3BrO3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[CH3:26][S:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].Cl.N1C=CC=CC=1.C(OCCO)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][C:3]([C:24]#[N:25])=[C:2]2[NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=1[S:27][CH3:26]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCOCC1
Reactant: CSc1ccccc1N
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccccc3SC)c(C#N)cnc2cc1OCCCN1CCOCC1

Procedure:
The method of Example 312 was used as well as 0.3 g of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile, 0.14 ml of 2-(methyl mercapto) aniline, 0.1 g of pyridine hydrochloride and 4.0 ml of 2-ethoxy ethanol. This afforded an oil which was purified by silica gel flash chromatography [methylene chloride/methanol (96:4) ] to give 0.16 g of the title compound as an off white solid, mp 179-180 C; mass spectrum (ES, m/e):M+H465.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:41]4[CH2:40][CH2:39][N:38]([CH:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[CH2:43][CH2:42]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCN(C2CCN(C)CC2)CC1
Temperature: 105 °C
Yield: 69.6 %

Procedure:
Following the procedure of Example 11, a mixture of 220 mg (0.5 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile, 290 mg (1.6 mmol) of 1-(1-methylpiperidin-4-yl)piperazine in 1.2 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 20 hours to yield the crude product. Purification by silica gel chromatography (gradient 9:1 methylene chloride/methanol to 85:15 methylene chloride/methanol) gives 210 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxy-7-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]quinoline-3-carbonitrile as a beige solid, mp 220-226° C. (shrinks at 205° C.).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:21][CH:22]=1.[I:28]I>O1CCCC1.CCCCCC>[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH2:24][CH:25]2[CH2:26][CH2:27]2)=[C:21]([I:28])[CH:22]=1
Reactant: Clc1ccc(OCC2CC2)nn1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1cc(I)c(OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 0.988 mL 2,2,6,6-tetramethylpiperidine in 10 mL tetrahydrofuran was added 3.534 mL of a 1.6M solution of n-butyl lithium in hexane at ambient temperature and the mixture was stirred at room temperature for 30 min. To this solution was added rapidly a pre-cooled (−75° C.) solution of 0.300 g 3-chloro-6-cyclopropylmethoxy-pyridazine in 10 mL tetrahydrofuran at −75° C. After 5 minutes, a precooled solution of 0.701 g iodine in 10 mL THF was added rapidly. The reaction mixture was stirred at −75° C. for 30 minutes and then quenched with a saturated aqueous solution of ammonium chloride and diluted with ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 0.206 g of the title compound as light yellow solid, MS 310.9 (M+H)+.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[C:18](Br)[C:17]=1[CH3:25])C(=O)OC(C)(C)C)=O)(C)(C)C.CC([O-])=[O:28].[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.OO.[OH-].[Na+].Cl.O1CCOCC1>CS(C)=O.C1COCC1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:8][C:16]1[C:17]([CH3:25])=[C:18]([OH:28])[CH:19]=[C:20]([CH3:23])[C:21]=1[F:22]
Reactant: Cc1cc(Br)c(C)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Reactant: CC(=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)c(C)c(N)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A mixture of tert-butyl N-tert-butoxycarbonyl-N-(3-bromo-6-fluoro-2,5-dimethylphenyl)carbamate (0.81 g, 1.94 mmol, 1.0 eq), Pd(dppf)Cl2 (763 mg, 0.19 mmol, 0.1 eq), KOAc (571 mg, 5.82 mmol, 3.0 eq) and bis(pinacolato)diboron (591 mg, 2.33 mmol, 1.2 eq) in DMSO (10 mL) under N2 was stirred at 80° C. overnight. After cooling to room temperature, the reaction was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford a crude residue. The residue obtained was dissolved in THF (10 mL) and the solution cooled to 0° C. H2O2 (30% aqueous solution, 660 mg, 5.82 mmol, 3.0 eq) was added, followed by NaOH (1M aqueous solution, 5.82 mL, 5.82 mmol, 3.0 eq) the mixture was stirred for 10 min and allowed to warm to 10° C. The pH was adjusted to pH 5˜7 by addition of 3M HCl and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was dissolved in MeOH (8 mL) and cooled to 0° C. HCl in dioxane (4M, 12 mL, 48 mmol, 24.7 eq) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was then cooled to 0° C. and the pH adjusted to 5-6 by addition of 1M NaOH. The dioxane was removed in vacuo and the aqueous phase extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give a crude residue, which was purified by column chromatography (petroleum ether: EtOAc, 10:1) to give the title compound as a yellow solid (157 mg, 52%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.Cl.[C:18]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH2:19][OH:20].C(N(C(C)C)CC)(C)C>CS(C)=O.O>[OH:20][CH2:19][C:18]([N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]3[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=3)[CH:4]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: O=C(CO)N1CCNCC1
Reactant: N#Cc1cnc(Nc2cc(CCl)ccn2)s1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1cnc(Nc2cc(CN3CCN(C(=O)CO)CC3)ccn2)s1

Procedure:
2-{[4-(Chloromethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile (180 mg, 0.72 mmole) and 1-glycoloylpiperazine hydrochloride (259 mg, 1.44 mmole) were combined in DMSO (2 mL). To this was added diisopropylethylamine (0.38 mL, 2.15 mmole) at RT. After 3 hr the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 5-15% EtOH/EtOAc then 5-10% MeOH/CHCl3) gave the title compound as a pale yellow solid: 1H NMR (d6-DMSO) δ12.19 (s, 1 H), 8.33 (d, 1 H, J=5.1 Hz), 8.32 (s, 1 H), 7.14 (s, 1 H), 7.0 (d, 1 H, J=5.2 Hz), 4.54 (t, 1 H, J=5.6 Hz), 4.08 (d, 2 H, J=5.6 Hz), 3.55 (s, 2 H), 3.49 (s, 2 H), 3.36 (s, 2 H), 2.38 (s, 4 H); MS [M+H]+=359.1285.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](O)=[O:23])[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:61]1[C:65]([CH2:66][CH2:67][NH2:68])=[N:64][N:63]=[N:62]1.CCN(CC)CC>CN(C=O)C>[C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](=[O:23])[NH:68][CH2:67][CH2:66][C:65]5[N:61]=[N:62][NH:63][N:64]=5)[CH2:20][CH2:21]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Reactant: NCCc1nnn[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NCCc4nn[nH]n4)CC3)n21
Temperature: 0 °C
Yield: 80.7 %

Procedure:
1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (50 mg, 0.09 mmol) and HATU (57 mg, 0.15 mmol), were combined with a heterogeneous solution of 2-(1H-tetrazol-5-yl)-ethylamine formiate (45 mg, 0.26 mmol) in anhydrous DMF (1 mL) and cooled to 0° C. Et3N (0.043 mL, 0.3 mmol) was added to the reaction. After 18 h the reaction slowly warmed to room temperature. The crude reaction solution was filtered and purified via reverse HPLC to yield 45 mg of the title compound as a white solid, m/z 619.5 [M+1]+).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=O)[CH2:27]1)=[O:25].[OH:33][C:34]1[C:35]([C:40]([NH:42][NH2:43])=O)=[N:36][CH:37]=[CH:38][CH:39]=1>ClCCl>[Cl:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]([N:26]1[CH2:31][CH2:30][N:29]2[C:40]([C:35]3[C:34]([OH:33])=[CH:39][CH:38]=[CH:37][N:36]=3)=[N:42][N:43]=[C:28]2[CH2:27]1)=[O:25]
Reactant: NNC(=O)c1ncccc1O
Reactant: O=C1CN(C(=O)c2cccc(C(F)(F)F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ncccc2O)C1
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (204 mg, 1.076 mmol) was added to a solution of the 4-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-piperazinone (I1)(300 mg, 0.978 mmol) in Dichloromethane (DCM) (6 mL) and the reaction was stirred for 1 h. To this was added the 3-hydroxy-2-pyridinecarbohydrazide (I93) (180 mg, 1.174 mmol) and the reaction was stirred for 2 hrs. The solvent was evaporated and 1-butanol (6.00 mL) was added. The mixture was heated at reflux for 3 h. After cooling the solvent was evaporated and the residue was partitioned between water/EtOAc. The organic layer was passed through a phase sep. cartridge and the solvent evaporated to afford an amber oil. This was purified by MDAP to afford a colourless solid of desired material in 90 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11]N(C)C.[C-:15]#[N:16].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:15]#[N:16]
Reactant: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c[nH]c2ccc(Cl)cc12
Temperature: 140 °C
Yield: 62.1 %

Procedure:
A solution of aqueous formaldehyde (37%, 2.95 mL, 66.0 mmol) and dimethylamine (40%, 5.30 mL, 66.0 mmol) in 20 mL EtOH was cooled to 0° C. 5-Chloroindole (4.0 g, 26.4 mmol) was dissolved in a HOAc:EtOH mixture (1:1, 40 mL) and added dropwise to the reaction mixture. After stirring at this temperature for 2 h, the mixture was allowed to warm to room temperature and stir overnight. The mixture was added to a sat'd solution of NaHCO3. 1 N NaOH was added until the pH was between 9-10. The resulting mixture was extracted with CH2Cl2 (3×). The organics were combined and washed with a sat'd aq. NaCl, dried over MgSO4, filtered and concentrated in vacuo to give 4.65 g (85%) of 5-chloro-3-[(dimethylamino)methyl] indole as a yellow powder. Without further purification, 5-chloro-3-[(dimethylamino)methyl] indole (4.65 g, 22.4 mmol) was dissolved in dimethylformamide (80 mL) at room temperature with stirring. To this was added KCN (2.18 g, 33.5 mmol) in H2O (10 mL). The mixture was warmed to 140° C. and stirred for 14 h. H2O was added and the mixture was extracted with EtOAc (2×). The organics were combined and washed with sat'd brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by SiO2 flash chromatography (3:2, Heptane: EtOAc) to give 2.65 g (63%) of 5-chloroindole-3-acetonitrile. 1H NMR (DMSO-d6, 300 MHz) δ 11.30 (br s, 1 H), 7.63 (s, 1 H), 7.42-7.38 (m, 2 H), 7.05 (d, J=6.0 Hz, 1 H), 5.70 (s, 2 H),
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)[NH2:25].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:13]1([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:25][C:24]3[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:22]([O:21][CH3:20])[CH:23]=3)=[CH:3][C:4]=2[C:16]([F:19])([F:18])[F:17])(=[O:10])=[O:9])[CH2:15][CH2:14]1
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Reactant: COc1cc(N)cc(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(Nc2ccc(S(=O)(=O)NCC3CC3)c(C(F)(F)F)c2)cc(OC)c1
Reaction time: 6 h
Yield: 48 %

Procedure:
Mixture of 4-bromo-N-cyclopropylmethyl-2-trifluoromethylbenzenesulfonamide (295 mg, 0.82 mmol), 3,5-dimethoxyaniline (142 mg, 0.92 mmol), Pd(OAc)2 (26 mg, 0.11 mmol), BINAP (70 mg, 0.11 mmol) and cesium carbonate (395 mg, 1.21 mmol) in 15 ml toluene was relaxed for 6 hours. Toluene was evaporated in vacuum and crude oil was purified by Combiflash (PE-THF). Yield 48%
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2([C:35](O)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:10]([NH:12][C:35]([C:29]2([O:28][C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:36])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)C1(Oc2ccc(Cl)cc2)CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)C1(Oc2ccc(Cl)cc2)CCCCC1)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (Diastereomer α, Reference Example 1) (60 mg, 0.19 mmol) and 1-(4-chlorophenyloxy)cyclohexanecarboxylic acid (60 mg, 0.24 mmol) in 1 mL of methylene chloride was added N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) and tris(pyrrolindinyl)phosphonium hexafluorophosphate (0.10 g, 0.19 mmol). After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column eluted with 6:1 hexane/ether to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.22 (d, 2H), 7.19 (d, 2H), 7.03 (d, 2H), 6.99 (d, 2H), 6.91 (d, 2H), 6.71 (d, 2H), 4.24 (m, 1H), 2.99 (dd, 1H), 2.80 (ddd, 1H), 2.63 (dd, 1H), 2.3-1.2 (m, 10H), 0.82 (d, 3H). LC-MS: m/e 530 (M+H)+ (5.0 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][C:12]([NH:14][C:15]([CH3:31])([CH2:21][C:22](=O)[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[C:16]([O:18]CC)=[O:17])=[O:13])=[CH:5][CH:4]=1.O.[OH-].[Li+]>C1COCC1.O.CC(O)=O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:11]2[C:12](=[O:13])[NH:14][C:15]([CH3:31])([C:16]([OH:18])=[O:17])[CH2:21][C:22]=2[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:32])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)(CC(=O)c1ccc(C)cc1)NC(=O)CC(=O)Nc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(NC(=O)C2=C(c3ccc(C)cc3)CC(C)(C(=O)O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of Intermediate 102C (0.033 g, 0.075 mmol) in THF (8 mL) and water (1.600 mL) was added lithium hydroxide monohydrate (3.77 mg, 0.090 mmol) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was acidified with AcOH (5 drops) and diluted with EtOAc (10 mL) and water (3 mL). The phases were separated and the aqueous phase was extracted with EtOAc (10 mL). The organic phases were combined and dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (0.0213 g, 72%) as a white solid. LCMS Anal. Calc'd for C22H22N2O5 394.15, found [M+H] 395.0.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2)nc1Cl

Procedure:
A mixture of the product from Step 1 (54 g, 0.26 mol), p-chlorophenol (31.7 g, 0.25 mol) and cesium carbonate (101.4 g, 0.31 mol) in anhydrous DMF (1.0 L) was stirred at 25° C. for about 2 h or until less than 5% of the starting material remained. The reaction mixture was then poured into water (2.5 L) and extracted with ethyl acetate (2×800 mL). The organic layer was washed with water (2×300 mL) and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel eluting with 7:1 hexane:ethyl acetate to afford the title product.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16]C(=O)C)=[CH:9][C:10]=2[O:12][C:13](=O)C)[O:5][C:4](=[O:20])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CI>C(COC)OC>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:16])=[CH:9][C:10]=2[O:12][CH3:13])[O:5][C:4](=[O:20])[CH:3]=1
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(C)cc(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: COCCOC
Product: COc1cc(O)cc2oc(=O)cc(C)c12

Procedure:
The 4-methyl-5,7-diacetoxycoumarin (XXXIV) was dissolved in dimethoxyethane (80 ml) and a solution of dry K2CO3 (6.6 g) and methyl iodide (3 ml) was added. The mixture was refluxed for 6 h, the solvent was evaporated and the residue, after addition of water:methanol (50:50; 80 ml), was heated to reflux 20 min. By evaporation of the MeOH under reduced pressure and by cooling a precipitate was formed, which by crystallization of first from MeOH and then from Me2CO gave 4-methyl-5-methoxy-7-hydroxycoumarin (XXXV; 1.52 g; m.p. 261°-3° C.). ##STR38##