Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.CN(C)[CH:21]=[O:22].C[O-].[Na+].CNC>O>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][CH:21]=[O:22])[CH2:10][CH2:11]2
Reactant: Nc1ccccc1N1CCc2cc(Cl)ccc21
Reactant: CN(C)C=O
Agent: CNC
Agent: C[O-]
Agent: Cl
Solvent: O
Product: O=CNc1ccccc1N1CCc2cc(Cl)ccc21

Procedure:
A stirred mixture, under N2, of 24.3 g of 1-(2-amino-phenyl)-5-chloroindoline hydrochloride, of Example 5, and 150 ml of dry dimethylformamide (DMF) is immersed in a 100° C. pre-heated oil bath. Solution occurs at 60° C. when 14.4 g of solid sodium methoxide is added in one portion. The mixture is rapidly heated to reflux and kept there for 45 minutes during which dimethylamine evolves copiously. The reaction mixture is then treated, in portions and without further heating, with 2 liters of water to precipitate the product as an oil. The water is removed by decantation. The oil is taken up in chloroform, extracted with H2O, with 3N--HCl, once again with H2O, dried over sodium sulfate and concentrated to a hard glass. This is dissolved in hot benzene (charcoal) to which hexane is added. The solid of 5-chloro-1-(2-formamidophenyl)indoline, m.p. 126°-129° C. is collected.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[CH:2].C([Li])CCC.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1.[Cl-].[NH4+]>[CH2:19]([O:18][C:16](=[O:17])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1cccc(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1cccc(C)n1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of 2-Ethynyl-6-methyl-pyridine (0.5 g, 4.3 mmol) in THF (20 mL) is cooled to −78° C. and treated with 1.6 M n-butyllithium in hexanes (2.9 mL, 4.7 mmol) and stirred for 0.5 hours. This solution is then treated with ethyl chloroformate (2.85 mL, 30 mmol) and stirred for 3 hours while the solution warms to room temperature The reaction is diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The solvent is concentrated to afford 0.67 g (83%) of desired product as a light yellow oil. UV (95% EtOH) λmax 286 nm (ε 10977), 238 nm (ε 9757). TOF MS ES+ exact mass calculated for C11H11NO2 (p+1): M/z=190.0868. Found: 190.0864.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+3]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][CH:6]([C:5]([OH:12])=[O:14])[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCOc2ccc(Cl)cc21
Agent: [Tl+3]
Product: O=C(O)C1COc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 6-chloro-4-chromanone (9.0 g, 0.049 mole) and thallium trinitrate (0.074 mole) absorbed onto K10 clay (75 g) by the method of Description 1, as a yellow solid (1.51 g, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.[H-].[Na+].[CH3:20]OCCOC.CI>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:20])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)Cc1ccc2cc(OC)ccc2c1
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CI
Product: COC(=O)C(C)c1ccc2cc(OC)ccc2c1

Procedure:
To a mixture of 22 g. of methyl 2-(6-methoxy-2-naphthyl)acetate (prepared by treating 20.5 g. of 2-(6-methoxy-2-naphthyl)acetic acid with 4.5 g. of diazomethane in ether), and 2.5 g. of sodium hydride in 150 ml. of 1,2-dimethoxyethane; 25 g. of methyl iodide are added. The reaction mixture is allowed to stand for several hours; then it is diluted with ethanol followed by water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered and evaporated to yield methyl 2-(6-methoxy-2-naphthyl)propionate.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: Cc1cccnc1Oc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: Cc1cccnc1Oc1ccc(C[C@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)cc1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-methyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:10][CH:11]=1.CS(C)=O.Cl.[OH-].[Na+]>O1CCCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:9]1[N:10]=[CH:11][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=1
Reactant: c1ccc(OCc2ccc(C3OCCO3)cn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=Cc1ccc(COc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 48.1 %

Procedure:
To a solution of 5-[1,3]dioxolan-2-yl-2-(pyridin-2-yloxymethyl)-pyridine (1.51 g, 5.85 mmol) described in Manufacturing Example 154-1-5 in tetrahydrofuran (15 mL) and dimethyl sulfoxide (10 mL) was added a 5 N hydrochloric acid aqueous solution (3 mL), which was stirred for 25 minutes at room temperature, and then for another 1 hour at 20 minutes at 60° C. A 5 N sodium hydroxide aqueous solution was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (603 mg, 48%).
Reaction SMILES: [CH:1](O)=[O:2].[CH3:4][O:5][C:6]([C:8]1([NH2:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>CN(C1C=CN=CC=1)C>[CH3:4][O:5][C:6]([C:8]1([NH:20][CH:1]=[O:2])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9]1)=[O:7]
Reactant: O=CO
Reactant: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Product: COC(=O)C1(NC=O)CCN(C(=O)OC(C)(C)C)C1

Procedure:
Added formic acid (200 mg, 4.34 mmol) to solution of 3-Amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1T) (900 mg, 3.688 mmol); 2-Chloro-4,6 dimethoxy-1,3,5-Triazine (CDMT) (800 mg, 4.556 mmol); DMAP (20 mg), and NMM (400 mg, 4 mmol) at room temperature, then stirred overnight. The solvent was evaporated and the residue extracted with MeCl2 (200 ml), washed with H2O (50 ml), dried over MgSO4, filtered and solvent evaporated yielding a solid which chromatographed on silica gel eluting with 5% MeOH/MeCl2 containing 2% NH4OH yielding 2T as a white solid (725 mg, 72%) LCMS (MH 273) Retention time=2.53 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16](I)[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:12](=[O:27])[N:13]2[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].[CH:37]([N:40]1[CH2:45][CH:44]2[CH2:46][CH:41]1[CH2:42][NH:43]2)([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N:43]2[CH2:42][CH:41]3[CH2:46][CH:44]2[CH2:45][N:40]3[CH:37]([CH3:39])[CH3:38])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:12](=[O:27])[N:13]2[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: CC(C)N1CC2CC1CN2
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(I)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-iodo-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (EXAMPLE CCC34) and using 2-isopropyl-2,5-diazabicyclo[2.2.1]heptane (INTERMEDIATE ABA2) as described in EXAMPLE 80. Mass spectrum (ESI): 661.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1.Br[CH:25]([CH2:31][CH2:32][CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:25]([CH2:31][CH2:32][CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Reactant: CCCC(Br)C(=O)OCC
Product: CCCC(Oc1ccc(Cl)cc1C#Cc1cc(S(=O)(=O)CCC)ccc1C)C(=O)OCC

Procedure:
Following the general method as outlined in Intermediate 268, starting from 4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenol (Intermediate 267) and ethyl 2-bromovalerate, the title compound was obtained as a colorless sticky solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)C=CC=CC=1.[CH:36]([NH2:40])([CH2:38][CH3:39])[CH3:37]>>[CH:36]([NH:40][C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:14])([CH2:38][CH3:39])[CH3:37]
Reactant: CCC(C)N
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCC(C)NC(=O)SCCN

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (300 mg) and sec-butylamine (188 μl) were subjected to similar reactions to those described in References 2 and 4 to give 2-sec-butylaminocarbonylthioethylamine (crude formate: 227 mg). The product was dissolved in anhydrous methanol (5 ml). Triethylamine (342 μl) and mitomycin A (137 mg: 0.8 molar equivalent) were added to the reaction solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 30 (94 mg) in the form of grayish blue powders with a yield of 49%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:35][C:23]([F:22])([F:34])[C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring dichloromethane (50 mL) solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.90 g, 19.4 mmol), 4-(dimethylamino)pyridine (0.23 g, 1.9 mmol), and triethylamine (8.0 mL, 57 mmol) was added 4-(trifluoromethyl)benzenesulfonyl chloride (4.75 g, 19.4 mmol). The reaction mixture was stirred for two hours at room temperature. The reaction was quenched with 1.0 M hydrochloric acid (100 mL) and extracted with diethyl ether (2×250 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. It was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=8.2 Hz, 2H), 7.83 (d, J=8.2 Hz, 2H), 4.79 (tt, J=7.6, 3.6 Hz, 1H), 3.62 (ddd, J=13.6, 7.4, 4.0 Hz, 2H), 3.27 (ddd, J=13.8, 7.8, 3.9 Hz, 2H), 1.86-1.79 (m, 2H), 1.75-1.68 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:28]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:46][C:7]1[C:6]2[N:28]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:5]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])=[CH:10][C:9]=2[N:8]=1
Reactant: CCc1nc2cnc3cc(CCN4C(=O)c5ccccc5C4=O)ccc3c2n1CC(C)(C)O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(CCN4C(=O)c5ccccc5C4=O)ccc3c2n1CC(C)(C)O
Reaction time: 18 h

Procedure:
2-{2-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethyl}-1H-isoindole-1,3(2H)-dione (1.90 g, 4.29 mmol) in dichloromethane (75 mL) was combined with 3-chloroperoxybenzoic acid (60% pure, 1.24 g, 4.72 mmol) and the reaction was stirred for 18 hours. Concentrated ammonium hydroxide (40 mL) was added and the mixture was vigorously stirred for an additional 10 minutes. p-Toluenesulfonyl chloride (900 mg, 4.72 mmol) was added and the mixture was stirred for an additional 1 hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×50 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% gradient of methanol in dichloromethane) provided 1.05 g of 2-{2-[4-amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethyl}-1H-isoindole-1,3(2H)-dione as an off-white foam. MS (APCI) m/z 458 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:21]1([NH:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:20]=1
Reactant: O=C(O)c1cnc(C2CCCCC2)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
A mixture of 2-cyclohexyl-pyrimidine-5-carboxylic acid (100 mg, 0.48 mmol), 1-hydroxybenzotriazole (74.2 mg, 0.55 mmol), and PS-DCC (505 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 minutes, and aniline (30 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours, PS-trisamine (388 mg, 3.75 mmol/g, 1.45 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated in vacuo to afford 2-cyclohexyl-pyrimidine-5-carboxylic acid phenylamide (45.6 mg, 51%) as a solid. MS: 282 (M+H); IC50=4960 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](B(O)O)=[CH:7][C:6]=2[CH:13]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH2:33]C)=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:15]3[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=4)[N:16]=3)=[CH:7][C:6]=2[CH:13]=1
Reactant: OB(O)c1cc2cc(Cl)ccc2o1
Reactant: CCOC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4cc(Cl)ccc4o3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of 5-chlorobenzofuran-2-ylboronic acid (281 mg, 1.43 mmol) in dioxane (6 mL) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140 mg, 0.48 mmol), K3PO4 (303 mg, 1.44 mmol), Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 3 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(5-chlorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (152 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[C:19]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[O:13])[N:4]=1>CO.CN(C)C=O.[Pd].[O-][V](=O)=O.[Na+]>[NH2:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([NH:14][C:12]([NH:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[N:8]=[C:3]([O:2][CH3:1])[N:4]=2)=[O:13])(=[O:16])=[O:17])[C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Agent: O=[V](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(N)cccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Reaction time: 0.17 h

Procedure:
50 mg (113 μmol) of methyl 2-[([(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]-carbonylamino)sulfonyl]-6-nitrobenzoate are suspended in a mixture of 3 ml of methanol/dimethylformamide (5:1), admixed with 10 mg of palladium on activated carbon (5%) and 1 mg (8.20 μmol) of sodium (meta)vanadate and hydrogenated under atmospheric pressure and at room temperature for 3 h. The mixture is then filtered off, the filtrate is concentrated and the residue is taken up in water and adjusted to pH 1.5 using 3 N aqueous hydrochloric acid solution. The precipitate is stirred in an ice-bath for 10 min and then filtered off with suction and dried under reduced pressure. This gives 41 mg (87% of theory) of methyl 2-amino-6-[([(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]carbonylamino)sulfonyl]benzoate of m.p. 129-134° C. (decomp.).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I-:35].[K+].[OH-].[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(#N)C>[I:35][C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: O=N[O-]
Solvent: O
Solvent: CC#N
Product: O=C1Nc2ncccc2[C@]12Cc1ccc(I)cc1C2
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (107 g, 1.55 mol) in water (500 mL) was added dropwise over 15 min to a solution of (2R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (195 g, 0.776 mol) and p-toluenesulfonic acid (443 g, 2.33 mol) in acetonitrile (1.94 L) at 23° C. After stirring for 30 min, a solution of potassium iodide (322 g, 1.94 mol) in water (500 mL) was then added over 15 minutes. The resulting mixture was stirred at 23° C. for 40 minutes, then diluted with water (2 L) and basified by the addition of solid NaOH (98.0 g, 2.44 mol) with stirring. Iodine by-product was reduced by the addition of 10% aqueous sodium thiosulfate solution and stirring for an additional 30 minutes. The solids were collected by filtration, washed with water, and dried under nitrogen atmosphere to give the title compound, which was used without further purification. MS: m/z=363.1 (M+1).
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][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[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][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CN2CCCCC2)c1

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(piperidin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol) and piperidine (0.049 mL; 0.5 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished the title compound as a white solid, quantitatively.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.CNC1CCCCC1NC>[Cu]I.C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:3]=1
Reactant: COC(=O)c1ccc2c(F)c[nH]c2c1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(F)cn(-c3ccc(F)cc3)c2c1
Temperature: 95 °C

Procedure:
Compound 21a (51 mg, 0.264 mmol), CuI (5 mg, 0.0264 mmol) and K3PO4 (40 mg, 0.66 mmol) were combined in a sealed reaction tube and the vial was back-flushed with N2. 4-Fluoro-iodobenzene 21b (0.0394 mL, 0.264 mmol) and N,N′-dimethylcyclohexane-1,2-diamine (0.0125 mL, 0.0792 mmol) were added via syringe, followed by toluene. The reaction mixture was heated at 95° C. for 6 h. The reaction was partitioned between EtOAc and water. The organic phase was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give compound 21c.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].CN(C)C=O.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>[Cu]I.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:34]=[N:35][NH:36][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1cccc(C)n1)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2cccc(C)n2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 2.94 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-(6-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 112) (90 mg, 0.282 mmol) and copper(I) iodide (5.37 mg, 0.028 mmol) then filled with N,N-dimethylformamide (DMF) (0.9 mL) and methanol (0.100 mL) and the resulting mixture was treated with trimethylsilyl azide (0.150 mL, 1.127 mmol). The flask was flushed with nitrogen then the mixture was stirred at 100° C. for 1 hr under microwave irradiation then cooled to room temperature. Most of the methanol was removed in vacuo and the remaining organic phase was purified by MDAP (modifier: ammonium bicarbonate) to give (2S,4R)-1-acetyl-2-methyl-N-(6-methyl-2-pyridinyl)-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinamine (3 mg, 8.28 μmol, 2.94% yield) as a colourless glass.