Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.[I-].[K+].[C:23](=[O:26])([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:7][C:4]3[CH:5]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)([CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=3)[C:23](=[O:26])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=C([O-])[O-]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)Cc1cccc(Cl)c1
Temperature: 60 °C

Procedure:
A mixture of 6-chlorooxindole (0.42 g, 2.5 mmol) (Crescent), 3-chlorobenzyl bromide (1.13 g, 5.5 mmol) (Aldrich), potassium iodide (1.04 g, 6.25 mmol) and potassium carbonate (1.04 g, 7.5 mmol) in acetone (10 mL) was heated at 60° C. for 20 hours in a sealed tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from ethyl acetate-hexanes to give 6-chloro-3,3-bis-(3-chlorobenzyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.31 g, 29.8%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:10]=[N:11][CH:12]=1.C(Cl)Cl>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[N:11][CH:12]=1
Reactant: CN1CCC[C@H]1c1cncc(OCCNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC[C@H]1c1cncc(OCCN)c1
Yield: 84.9 %

Procedure:
Preparation 12a: (S)-tert-butyl 2-(5-(1-Methylpyrrolidin-2-yl)pyridin-3-yloxy)ethylcarbamate (preparation 11) (105 mg, 0.33 mmol) was stirred in trifluoroacetic acid (1 mL) and DCM (5 mL) for 1.5 h. The reaction mixture was evaporated, then co-evaporated with DCM (×5) and 20% ammonia in MeOH. The crude product was purified by flash chromatography (5% [20% ammonia in MeOH] in DCM) to give the title compound as a yellow oil (62 mg, 85%).
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(OCC)C)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10](C=O)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:46][OH:47].[C:48]([O-])(O)=O.[Na+].[CH3:53][OH:54]>>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:46]([O:54][CH3:53])[O:47][CH3:48])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCCc1nc2cc(-c3ccccc3)c(C=O)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: CCCCc1nc2cc(-c3ccccc3)c(C(OC)OC)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 79.4 %

Procedure:
0.1 g(0.000169 mole) of the compound obtained in step 11 and 0.36 g(0.00338 mole) of trimethylformate were dissolved in 5 ml of methanol and to the resulting solution was added 0.5 ml of 3% anhydrous HCl/MeOH. The resultant was refluxed for 2 hours and cooled. 5 ml of saturated NaHCO3 solution was added to the reaction solution. The resulting solution was evaporated under reduced pressure to remove methanol and thereafter extracted with ethyl acetate(5 ml×4). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was recrystallized from hexane-methylene chloride to obtain 75 mg of the title compound in a white solid form(yield 79.4%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1N=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[N:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][CH:16]=1.Br[C:24]1N=C(C=O)C(F)=CC=1>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:24]=[CH:7][C:6]([C:15]2[N:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: O=Cc1nc(Br)ccc1F
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Solvent: CO
Product: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
The title compound was prepared using procedure similar to that described for Example 28A, substituting 4-(trifluoromethyl)phenylboronic acid for 6-(trifluoromethyl)pyridin-3-ylboronic acid and 6-bromopicolinaldehyde for 6-bromo-3-fluoropicolinaldehyde. MS (ESI+) m/z 283.9 (M+H+MeOH); 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.46-8.38 (m, 3H), 8.21 (t, J=7.7, 1H), 8.00-7.89 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27]C(O)=O)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:34](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[ClH:19].[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][NH2:34])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cl
Product: NC[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Temperature: 0 °C

Procedure:
In 5 ml of dimethylformamide was dissolved 1.0 g of trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid obtained obtained in Reference Example 5. To the solution was added 0.3 ml of triethylamine, to which was added dropwise, while stirring under ice-cooling, 0.6 g of diphenylphosphoryl azide. The reaction mixture was stirred for one hour at room temperature, which was then poured into ice-water. The mixture was subjected to extraction with ether. The organic layer was washed with water and dried, which was then concentrated under reduced pressure. The concentrate was dissolved in 100 ml of benzene, which was heated for 30 minutes under reflux. The reaction mixture was concentrated under reduced pressure. To the concentrate was added 6 ml of conc. hydrochloric acid, and the mixture was heated for one hour under reflux. The reaction mixture was concentrated under reduced pressure. The concentrate was made alkaline by the addition of a 5% aqueous solution of potassium carbonate, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. To the residue was added an ethanol solution of 4N hydrochloric acid to lead it to hydrochloride to give 0.85 g of [trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]methylamine hydrochloride as crystals, m.p. 245°-250° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:37])[CH2:29][NH:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O>O1CCCC1.O.C(OCC)C>[C:3]([CH:5]=[CH:14][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:37])[CH2:29][NH:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:4]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a suspension of 0.4g (10.4 mmol) of sodium hydride (washed three times with hexane) in 2 mL of tetrahydrofuran was added 1.6 mL (10.4 mmol) of diethyl cyanomethylphosphonate. The mixture was stirred at ambient temperature for 15 minutes. To the mixture was added a solution of 3.0 g (8.7 mmol) of material from Example 45 in 15 mL of tetrahydrofuran. After stirring for two hours, the mixture was diluted with 25 mL of water and extracted three times with 20 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (150 g of silica gel, 35% ethyl acetate/hexane) of the residue gave a white solid which was suspended in ethyl ether, filtered and dried in vacuo to afford 2.5 g (79%) of the title compound.
Reaction SMILES: [Si]([O:8][C@H:9]([C:45]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:56])[NH:50]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:44])[C@H:22]1[C@H:26]2[CH2:27][CH2:28][C@@H:23]1[C@H:24]([O:29][C:30](=[O:43])[C:31]([OH:42])([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[CH2:25]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[OH:8][C@H:9]([C:45]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:56])[NH:50]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:44])[C@H:22]1[C@H:26]2[CH2:27][CH2:28][C@@H:23]1[C@H:24]([O:29][C:30](=[O:43])[C:31]([OH:42])([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[CH2:25]2
Reactant: CN(CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCCCCCCCCNC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Reaction time: 0.17 h

Procedure:
A solution of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-({9-[(R)-2-(tert-butyldimethylsilanyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]-nonyl}methylamino)bicyclo[2.2.1]hept-2-yl ester (72 mg, 0.087 mmol) and triethylamine trihydrofluoride (60 μL, 0.37 mmol) was stirred in THF/DCM (1:1, 2 mL) at ambient temperature overnight. The reaction mixture was neutralised with satd NaHCO3 (aq) and extracted with DCM. The organic layer was concentrated to dryness to afford a green/brown oil, which was purified by preparative HPLC (system 1, 15% B+1% B/min for 20 min, then 6% B/min for 10 min). The fractions containing pure product were concentrated, neutralised with satd NaHCO3 (aq), and extracted with THF. After concentration in vacuo a light brown oil was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][O:9][CH:10](Cl)Cl)=[CH:4][CH:3]=1.[P:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[O:16]CC.[CH2:25](Cl)[CH3:26]>CCOCC.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][O:9][CH:10]([P:15](=[O:16])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])[P:15](=[O:16])([O:22][CH2:25][CH3:26])[O:19][CH2:20][CH3:21])=[CH:4][CH:3]=1
Reactant: CCCl
Reactant: Clc1ccc(OCCOC(Cl)Cl)cc1
Reactant: CCOP(OCC)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(OCCOc1ccc(Cl)cc1)P(=O)(OCC)OCC

Procedure:
Anhydrous zinc chloride (10 g) was added at 150° C. to a mixture of dichloromethyl 2-(p-chlorophenoxy)-ethyl ether (5.1 g) and triethyl phosphite (6.9 ml). When the evolution of ethyl chloride ceased, the mixture was cooled, taken up in ether (250 ml), washed with aqueous sodium bicarbonate, dried and evaporated. Unreacted triethyl phosphite was removed in vacuo, and the crude product was used in the next step without further purification.
Reaction SMILES: [Li+].C[Si]([N-][Si:7]([CH3:10])(C)C)(C)C.Br[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16].CC=C[CH2:20][CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[Li+].[B-](CC)(CC)CC>C1COCC1.C(Cl)Cl>[SiH:7]([CH2:15][CH3:16])([CH2:20][CH3:21])[CH2:10][CH3:23].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[CH3:12][CH:13]=[CH:14][CH2:15][CH3:16]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC/C=C\CBr
Agent: CC=CCC
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CC[SiH](CC)CC

Procedure:
To a stirred solution of 7a (9.47 g, 29.7 mmol, 1 equiv) in anhydrous THF at −78° C. under N2 was added a 1 M solution of LiHMDS in THF (33 mmol, 33 mL, 1.1 equiv) followed by cis-1-bromo-2-pentene (4.21 mL, 35.6 mmol, 1.2 equiv), afforded a mixture of diastereomers of the lactam 7b (R9′=2-pentene) (43.2%) after silica gel purification. The lactam 7b (3.96 g, 10.22 mmol) was reduced to the pyrrolidine 7c (R9′=2-pentene) by the two-step sequence involving superhydride® reduction of the lactam to the hemiaminal, at −78° C. in anhydrous THF, and the subsequent reduction of the hemiaminal with Et3SiH/BF3OEt2 in anhydrous DCM at −78° C., affording 7c (R9′=2-pentene) (71%) after silica gel purification. The pyrrolidine 7c (2.71 g, 7.26 mmol) and 10% palladium on carbon (560 mg) in anhydrous methanol (30 mL) was subjected to Parr hydrogenolysis at 50 psi for 5 h. The reaction mixture was filtered through a celite pad and washed several times with methanol. The combined washings and filtrate were evaporated to dryness, affording, without further purification, a colorless oil 7d (R9=pentyl) (1.68 g, 80%); TLC: Rf=0.3 [Solvent system: DCM:hexanes:MeOH (6:5:1)]. MS (ESNEG): 284.5 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:28])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (0.05 g, 0.176 mmol), morpholine-4-carbonyl chloride (26.3 mg, 0.176 mmol) and N,N-diisopropylethylamine (68.1 mg, 92.0 μL, 0.527 mmol) were combined with CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hr and monitored by LC/MS. The crude product was purified using preparative reverse-phase HPLC, giving the desired product morpholine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide. MS calcd. for C21H21ClN3O3 [(M+H)+] 398.1, obsd. 398.0.
Reaction SMILES: [CH:1]1[C:6]([C:7]#[N:8])=[CH:5]C=[C:3]([NH2:9])[CH:2]=1.S(Cl)([Cl:13])(=O)=O.[OH-].[Na+].[CH:17]([Cl:20])(Cl)Cl>>[Cl:13][C:2]1[CH:1]=[C:6]([CH:5]=[C:17]([Cl:20])[C:3]=1[NH2:9])[C:7]#[N:8]
Reactant: ClC(Cl)Cl
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(Cl)c(N)c(Cl)c1

Procedure:
P-Aminobenzonitrile (11.8 g) (ex Aldrich) in dry chloroform (250 ml) under nitrogen was treated with sulphuryl chloride (4.05 g) (ex BDH) maintaining reaction temperature below 35°. After 2 hours at reflux the mixture was poured onto ice and made alkaline with 2M sodium hydroxide solution. Work up in the usual manner gave 3,5-dichloro-4-aminobenzonitrile (18.2 g) NMR 1H 7.35(2H,s), 4.70(2H,bs).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: COC(=O)c1ccc(Oc2ccc(N)cn2)cc1

Procedure:
Intermediate B-32 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and methyl 4-hydroxybenzoate as starting materials. MS (M+1): 245.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]([C:10]1(Cl)[C:14](=[O:15])[CH:13]=[CH:12][S:11]1)=[O:9]>C(Cl)Cl>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][C:14]=1[OH:15])=[O:9]
Reactant: c1c[nH]cn1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Solvent: ClCCl
Product: COC(=O)c1sc(-n2ccnc2)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
Imidazole (710 mg, 10.4 mmol, 2 Eq.) and 2-Chloro-3-oxo-2,3-dihydrothiophene-2-carboxylic acid methyl ester (1.0 g, 5.19 mmol, 1.0 Eq.) were dissolved in anhydrous DCM (25 mL) and stirred at ambient temperature for 18 hours. The crude reaction mixture was partitioned between EtOAc (50 mL) and brine (50 mL), The aqueous phase was extracted with EtOAc (3×20 mL) and the combined organice extracts washed with brine (1×10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purifed by column chromatography (5% MeOH/DCM) and recrystalised from EtOAc/hexane to give the sub-title compound as a yellow powder (692 mg, 3.09 mmol 59%); 1H NMR (400 MHz, d-6 DMSO) δ 3.77 (3H, s), 7.02 (1H, s), 7.14 (1H, d), 7.74 (1H, d), 8.28 (1H, d), 10.82 (1H, br s).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 160-162° C.). MS(ES+) m/z 278 ([M+1]+, 100).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][NH:29][CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.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.Cl.[CH2:68]([N:70]([CH2:76][CH3:77])[CH2:71][CH2:72][C:73](O)=[O:74])[CH3:69]>CN(C=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][N:29]([C:73](=[O:74])[CH2:72][CH2:71][N:70]([CH2:76][CH3:77])[CH2:68][CH3:69])[CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)CCC(=O)O
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, Example 31-C, (120 mg, 0.26 mmol), HATU (198 mg, 0.52 mmol), DIEA (0.2 mL, 1.30 mmol) and DMF (5 mL) is added 3-diethylamino-propionic acid hydrochloride (47 mg, 0.26 mmol). After stirring at rt for 2 h the contents of the flask are partitioned between DCM and 10% aqueous LiCl. Organic layer is removed, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is then separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 581.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.40-8.48 (m, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.5 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.36-7.47 (m, 2H), 7.10 (dd, J=9.0, 2.1 Hz, 1H), 6.74 (d, J=3.8 Hz, 1H), 4.71-4.79 (m, 2H), 3.85-4.05 (m, 2H), 3.20 (d, J=5.8 Hz, 2H), 2.84-3.08 (m, 8H), 1.23 (q, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(O)(C(F)(F)F)=[O:14]>[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([OH:14])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: COc1cnc2ccccc2c1
Reactant: O=C(O)C(F)(F)F
Agent: O=[Pt]
Product: COc1cnc2c(c1)CCCC2O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 3-methoxyquinoline (1.06 g, 6.7 mmol) in TFA (22 mL) under nitrogen was added platinum oxide (225 mg, 1.3 mmol) and the suspension bubbled with hydrogen gas 16 h at 60° C. The mixture was then cooled to room temperature, neutralized to pH 12 with 10 N NaOH and extracted with CH2Cl2 (3×50 mL). The organic extracts were dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (ethyl acetate/hexane; 1:2) to give the desired 3-methoxy-5,6,7,8-tetrahydroquinoline (0.95 g, 87%). 1H NMR (CDCl3) δ 1.77 (m, 2H), 1.85 (m, 2H), 2.75 (t, 2H, J=6.0 Hz), 2.85 (t, 2H, J=6.0 Hz), 3.81 (s, 3H), 6.88 (d, 1H, J=1.5 Hz), 8.07 (d, 1H, J=1.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.CO.[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(N)c1

Procedure:
Methyl-2-(4-hydroxy-3-nitrophenyl)acetate (2.31 g, 10.9 mmol) was dissolved in THF (20 mL) and MeOH (20 mL) and 10% palladium on carbon (210 mg) was added slowly at RT. The reaction mixture was hydrogenated for 2 h at 39 psi hydrogen pressure, filtered through Celite and washed with MeOH. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/EA=2:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])(=O)C.[K+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:30]5[C:25]([CH3:24])=[N:26][CH:27]=[CH:28][CH:29]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: Cc1ncccc1B(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Temperature: 105 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
To 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (0.388 g, 0.992 mmol), 2-methylpyridin-3-ylboronic acid (0.176 g, 1.29 mmol), potassium acetate (0.389 g, 3.96 mmol), and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.049 mmol) was added DMF (20 mL) and water (1 mL). Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was allowed to stir at 105° C. for 24 hours before cooling, diluting with EtOAc, and filtering through a pad of celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 128 (115 mg, 28%). 1H NMR (400 MHz, DMSO) δ 8.44 (dd, J=24.8, 2.7, 2H), 8.10 (s, 1H), 7.69 (t, J=8.1, 1H), 7.35 (ddd, J=12.5, 7.9, 3.6, 2H), 7.19 (d, J=8.3, 1H), 5.74 (dt, J=13.2, 6.7, 1H), 4.44 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 2.53 (s, 3H), 1.48 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).