Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[C@H:4]([C@@H:12]([CH3:15])[O:13][CH3:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:17])=[O:16])[C@@H:12]([CH3:15])[O:13][CH3:14])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:25][CH2:24]1
Reactant: CO[C@H](C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CO[C@H](C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of N,N,O-trimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-threoninamide (670 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1140 mg) in 2-propanol (10 mL) was added piperidinium acetate (488 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (890 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.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:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ccc(F)cc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ccc(F)cc2c1Cl
Temperature: 110 °C

Procedure:
Prepared according to general Procedure E using 2,4-dichloro-6-fluoro-3-methylquinoline (250 mg, 1.1 mmol), 2-(tributylstannyl)pyridine (400 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.05 mmol) in toluene (5 mL) and heating at 110° C. overnight. After purification 4-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)quinoline was obtained as a white solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:14])[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:15]([CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](OC)=[O:20])(=O)[CH3:16].C[O-].[Na+].S(Cl)(Cl)=O>CO.CC(C)=O>[OH:20][C:19]1[C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:15]([CH3:16])[N:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:14]=1
Reactant: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 2-(4-nitrophenyl)ethanimidamide hydrochloride (0.22 g, 1.0 mmol), dimethyl acetyl-succinate (0.19 g, 1.0 mmol), and sodium methoxide (0.07 g, 1.3 mmol) in MeOH (10 mL) was refluxed for 15 hours. After cooling to room temperature, the separated solids were collected by suction and added to a pre-formed solution of thionyl chloride (0.65 mL, 8.9 mmol) in MeOH (7.5 mL). The resulting mixture was refluxed for 16 hours and then cooled to room temperature. Acetone was added and the precipitated solids were collected by suction, rinsed with acetone and dried under high vacuum for 4 hours to give methyl [4-hydroxy-6-methyl-2-(4-nitrobenzyl)-pyrimidin-5-yl]acetate (0.12 g, 38% yield) as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[C:29]([CH3:38])=[CH:28][C:27]2=[O:39])[CH2:20][CH2:19]1)[CH2:8][C:9](=[O:17])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:9](=[O:17])[CH2:8][NH:7][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[C:29]([CH3:38])=[CH:28][C:27]2=[O:39])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(CC(=O)Nc4ccccn4)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(NCC(=O)Nc4ccccn4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To 5 mL of a dichloromethane solution containing 0.11 g of tert-butyl(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2-oxo-2-(pyridin-2-ylamino)ethyl)carbamate, 5 mL of trifluoroacetic acid was added and stirred at room temperature for 30 min. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 13 with 20% aqueous sodium hydroxide solution under ice-cooling. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 83 mg of N- (pyridin-2-yl)-N2-(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)glycinamide as a light brown foam.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][S:27]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:36][CH:35]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(S(C)(=O)=O)cc3)nc12
Temperature: 150 °C
Yield: 59.6 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (125 mg, 292 μmol), 4-(methylsulfonyl)aniline (75.1 mg, 439 μmol), xantphos (50.8 mg, 87.7 μmol), Pd2(dba)3 (26.8 mg, 29.2 μmol) and cesium carbonate (191 mg, 585 μmol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled, filtered through celite, and the filtrate concentrated in vacuo. Purification by chromatography (silica, 20-75% ethyl acetate in hexanes) gave N-tert-butyl-2-(4-(methylsulfonyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 174 μmol, 59%) as a light yellow solid. (EI/CI) m/z: 518.3 [M+H].
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:7]1([O:13][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: CNS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)Oc1ccccc1
Temperature: 110 °C
Yield: 43 %

Procedure:
The reaction flask was charged with 34.1 g (0.20 mole) of methylaminosulfonyl chloride, 18.8 g (0.20 mole) of phenol and 150 ml of toluene. The dark, red solution was heated at 110° C. for 16 hours. The solution was cooled and washed with a solution of 16 g of sodium bicarbonate in 80 ml water. The toluene solution was washed with water then stirred with Type 3A molecular sieve powder and Norite "A" activated charcoal. After filtration, the filtrate was concentrated to 32.7 g of oil (87% crude yield). The oil was dissolved in 100 ml methylene chloride and chromatographed on silica gel. The main fraction was concentrated to an oil which solidified after chilling for 3 days. The solid was triturated with petroleum ether to give 16.1 g of solid, mp 43°-45° C. A recrystallization from a mixture of isopropyl acetate (2 ml/g) and petroleum ether (4 ml/g) gave 12.3 g of solid, mp 44°-46° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[CH:21]=[CH:22][C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26].C(NCC)C.[C:34]1([O:40][C:41]([N:43]2[CH:56]([C:57]#[CH:58])[C:55]34[O:59][C:50]3([C:51](=[O:60])[CH2:52][CH2:53][CH2:54]4)[C:49]3[CH:48]=[CH:47][C:46]([O:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:45][C:44]2=3)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1C=CC=CC=1.[Pd].[Cu]I>[C:34]1([O:40][C:41]([N:43]2[CH:56]([C:57]#[C:58]/[CH:21]=[CH:22]\[C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:55]34[O:59][C:50]3([C:51](=[O:60])[CH2:52][CH2:53][CH2:54]4)[C:49]3[CH:48]=[CH:47][C:46]([O:61][C:62](=[O:67])[C:63]([CH3:65])([CH3:64])[CH3:66])=[CH:45][C:44]2=3)=[O:42])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C[Si](C)(C)C#CC=CCl
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2cc(OC(=O)C(C)(C)C)ccc2C23OC12CCCC3=O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(=O)C21O3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
A mixture of Pd(PPh3 (4 (185 mg, 0.16 mmol), 1-chloro-4-(trimethylsilyl)-but-1-en-3-yne (0.776 g, 4.89 mmol), and diethylamine(0.51 L, 4.93 mmol) in degassed benzene (5 mL) was stirred at 25° C. for 15 minutes. The resultant solution was added to a mixture of Compound 230 (1.50 g, 3.26 mmol) and CuI (124 mg, 0.65 mmol) in degassed benzene (15 mL) via a syringe followed by stirring at 25° C. for one hour. The reaction mixture was quenched by saturated aqueous NH4Cl, extracted with ethyl ether (80 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 25 percent ethyl ether in petroleum ether) provided a solid product Compound 231 (0.606 g, 32 percent): Rf =0.43 (silica, 50 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2964, 1721, 1494, 1378, 1305, 1270, 1253, 1202, 1181, 1122, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ8.40 (d, J=8.7 Hz, 1 H, H1), 7.44-7.10 (m, 6 H, H4 and aromatic), 6.99 (dd, J=8.7, 2.4 Hz, 1 H, H2), 5.98 (d, J=1.5 Hz, 1 H, H6), 5.84 (d, J=11.1 Hz, 1 H, olefinic), 5.69 (br d, J =11.1 Hz, 1 H, olefinic), 2.81-2.66 (m, 2 H, H9), 2.41-2.26 (m, 2 H, H7), 2.10-1.86 (m, 2 H, H8), 1.33 (s, 9 H, COC(CH3)3), 0.22 (s, 9 H, SiC(CH3)3); MS (FAB+) m/e (rel intensity) 582 (M+H, 100), 525 (13), 460 (48), 406 (8), 360 (6(),320 (8), 279 (25), 246 (5); HRMS for C34H36NO6Si (M+H), calcd 582.2312, found 582.2322.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[O:10]=[C:11]1[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[CH2:13][NH+:12]1[CH3:20].C(=O)(O)[O-].[Na+]>O>[O:10]=[C:11]1[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[CH:13]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[OH:8])[N:12]1[CH3:20]
Reactant: CN1C[NH+](C)C(=O)N(C)C1=O
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)N(C)C(c2ccc(N)cc2O)N(C)C1=O

Procedure:
10.9 (0.1 mol) of m-aminophenol are added to a solution of 19.1 g (0.1 mol) of 2,4-dioxo-1,2,3,4-tetrahydro-1,3,5-trimethyl-s-triazinium chloride in 50 ml of water and the mixture is stirred for some minutes until a clear solution has been produced. 8 g of sodium bicarbonate are then added. 24 g (85) of the same compound as in Example 5 precipitate.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH3:5].C([BH3-])#N.[Na+]>>[F:12][C:9]1[CH:8]=[CH:7][C:6]([CH:4]([NH:3][O:2][CH3:1])[CH3:5])=[CH:11][CH:10]=1
Reactant: CON=C(C)c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONC(C)c1ccc(F)cc1

Procedure:
Reduction of 4′-fluoroacetophenone O-methyloxime with sodium cyanoborohydride as described in the preparation of 1-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8: 2) (51% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, d, J=6.5 Hz, CH3), 3.46 (3H, s, OCH3), 4.12 (1H, q, J=6.5 Hz, NCH), 5.59 (1H, broad, NH), 7.02 (2H, m, aromatics), 7.32 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 99-103° C. Anal. calcd for C9H12FNO—HCl: C, 52.56; H, 6.37; N, 6.81. Found: C, 52.45; H, 6.25; N, 6.55.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH:15]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:16]2.BrC1C=C2C(=CC=1)CC(NC(=O)C1C=CC(F)=CC=1)C2.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O.C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([NH:21][CH:15]2[CH2:16][C:17]3[C:13](=[CH:12][CH:20]=[C:19]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH:18]=3)[CH2:14]2)=[O:30])=[CH:24][CH:25]=1
Reactant: O=C(NC1Cc2cccc(Br)c2C1)c1ccc(F)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C(NC1Cc2ccc(Br)cc2C1)c1ccc(F)cc1
Agent: [Ba+2]
Solvent: O
Solvent: COCCOC
Product: O=C(NC1Cc2ccc(-c3ccc(F)cc3)cc2C1)c1ccc(F)cc1
Yield: 27 %

Procedure:
251 mg (1.8 mmol) 4-fluorobenzene boronic acid, 500 mg (1.5 mmol) of a mixture of N-(4-bromo-indan-2-yl)-4-fluoro-benzamide (relative amount 20%) and N-(5-bromo-indan-2-yl)-4-fluoro-benzamide (relative amount 80%), 708 mg (2.24 mmol) barium hydroxide octahydrate and 50 mg tetrakis(triphenylphosphine)-palladium were suspended in 10 ml of water and 10 ml of dimethoxyethane, under an argon atmosphere, and stirred over 2 h at 80° C. The mixture was poured onto ice water, the formed precipitate was filtered off and crystallized from ethyl acetate/hexane. 170 mg (27%) 4-fluoro-N-[5-(4-fluorophenyl)-indan-2-yl]-benzamide, mp.: 193° C., were obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[C:12]1[C@:28]2([CH3:29])[CH:15]([CH:16]3[C:25](=[CH:26][CH2:27]2)[C@:24]2([CH3:30])[C:19](=[CH:20][C:21](=[O:31])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][C@H:13]1[CH3:32])[O:7][Si](C)(C)C)(=[O:3])[CH3:2].Cl.C(=O)(O)[O-].[K+]>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6](=[O:7])[C@@H:12]1[C@:28]2([CH3:29])[CH:15]([CH:16]3[C:25](=[CH:26][CH2:27]2)[C@:24]2([CH3:30])[C:19](=[CH:20][C:21](=[O:31])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][C@H:13]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(O[Si](C)(C)C)=C1[C@H](C)CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C

Procedure:
The crude product from step 1 is dissolved in ethyl acetate, and slurried with aqueous 1N HCl until hydrolysis is complete. The aqueous acid is neutralized with aqueous potassium bicarbonate, and the ethyl acetate phase is dried, filtered, and concentrated to a semi-solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[N:18][C:17](O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>O>[Cl:3][C:17]1[N:18]=[N:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2ccc(O)nn2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-c2ccc(Cl)nn2)cc1
Yield: 40 %

Procedure:
With cooling with ice, 50 ml of phosphorus oxychloride was added to 10.00 g (49.5 mmol) of the obtained 6-(4-methoxyphenyl)-pyridazin-3-ol, and the reaction liquid was stirred under reflux for 6 hours. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.41 g (yield: 40%) of 3-chloro-6-(4-methoxyphenyl)-pyridazine as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3](=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]#[CH:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3](=[N:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:4]=[CH:5][S:26][C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: C#CC(=Nc1ccccc1)N(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(C(C=CSc1ccc(Cl)cc1)=Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60 %

Procedure:
N-methyl-N-phenyl-N′-phenylpropynamidine (0.23 g) was dissolved to chloroform (5 ml), chloroform (5 ml) solution of 4-chlorothiophenol (0.14 g) was added dropwise under ice-cooling and stirred for 14 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to obtain N-methyl-N-phenyl-N′-phenyl-3-(4-chlorophenylthio)acrylamidine (0.22 g) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22])[CH3:19]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(Cl)nc2ccsc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of Example 2 (3.0 g, 14.6 mmol) in 1,4-dioxane (200 mL) was added a solution of K2CO3 (4.0 g, 29.3 mmol) in water (40 mL). The almost clear solution was placed under nitrogen atmosphere and (1-Ethoxyvinyl)-tributylstannane (5.0 mL, 14.6 mmol) and PdCl2(PPh3)2 (500 mg, 0.731 mmol). The mixture was heated to 100° C. and stirred at 100° C. for 30 min under nitrogen atmosphere. After cooling to room temp. the 1,4-dioxane was removed i. vac. The residue was re-dissolved in DCM (100 mL) and water (50 mL) and transferred to a separating funnel. The aqueous layer was extracted with DCM (30 mL), the combined organic layers were washed with water (50 mL) and sat. brine (30 mL), dried over Na2SO4 and evaporated to dryness i. vac. The residue was purified by flash column chromatography (50 g SiO2 Isolute® pre-wetted with 1CV DCM) eluting with neat DCM collecting 12 mL fractions. Desired product eluted in fractions 10 to 20 with Rf=0.31 (DCM). By-products eluted in fractions 6 to 9 (Rf=0.59 in DCM) and fractions 21-31 ((Rf=0.14 in DCM). Fractions 10 to 20 were combined and evaporated to dryness i. vac. providing 2.28 g (65% yield) 2-chloro-4-(1′-ethoxy-vinyl)-thieno[3,2-d]pyrimidine as yellow powder of 95% purity.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: Cc1ccc(Cl)cc1[C@H](OCCN=[N+]=[N-])[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
(R)-tert-butyl 3-((R)-(2-azidoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (7 g, 17.1 mmoL) was dissolved in EtOAc (300 mL), 0.8 g of Pd(OH)2 was added and the air in bottle was replaced 3 times with H2, the reaction was stirred at rt for 3 hr. The solution was filtered and concentrated to give (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (6.2 g), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].C([Li])CCC.Cl.[C:20](=O)(O)[O-:21].[Na+]>CN(C=O)C>[F:11][C:3]1[C:2]([CH:20]=[O:21])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: O=C([O-])O
Reactant: Fc1c(Br)ccc2[nH]ncc12
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]ncc2c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-bromo-4-fluoro-1H-indazole (4 mmol) and sodium hydride (4.3 mmol) in an Argon-purged round-bottom flask was added dry THF (10 mL) at rt. The mixture was stirred at rt for 15 min, during which time it became homogeneous (dark brown). The mixture was then cooled to −78° C., and a solution of n-butyllithium (8.7 mmol, 1.6 M in hexane) was added dropwise. After stirring for 1 h at −78° C., DMF (2 mL) was added dropwise and the mixture was allowed to warm to rt. After 3 h, the mixture was cooled to 0° C. and carefully treated with 1N HCl (20 mL). After a few minutes, solid sodium bicarbonate was added to basify the mixture to pH9-10. The aqueous solution was extracted with EtOAc(2×), and the organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (0-40% EtOAc/hexanes) to give 4-fluoro-1H-indazole-5-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH:39]1([CH2:42]Br)[CH2:41][CH2:40]1>>[CH:39]1([CH2:42][N:34]2[CH2:35][CH2:36][C:31]3([C:28]4[C:27](=[CH:26][C:25]5[CH2:24][CH2:23][N:22]([C:20]([C:17]6[CH:18]=[CH:19][C:14]([C:3]7[CH:4]=[CH:5][C:6]([N:8]8[CH2:12][CH2:11][CH2:10][C:9]8=[O:13])=[CH:7][C:2]=7[CH3:1])=[CH:15][CH:16]=6)=[O:21])[C:30]=5[CH:29]=4)[O:38][CH2:37]3)[CH2:32][CH2:33]2)[CH2:41][CH2:40]1
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Reactant: BrCC1CC1
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(CC3CC3)CC2)CO4)cc1

Procedure:
The title compound was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and cyclopropylmethyl bromide using a similar procedure to Example 19, as a cream foam (52%). This was converted to the hydrochloride salt, isolated as a white powder.