Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C2N(N=C(Cl)N=2)C=CC=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.Cl[C:22]1[N:39]=[C:25]2[C:26]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1.[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=2)[NH2:50])[CH2:43][CH2:42]1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:26]2[C:25]3[N:24]([N:23]=[C:22]([NH:50][C:49]4[CH:51]=[CH:52][CH:53]=[C:47]([N:44]5[CH2:43][CH2:42][N:41]([CH3:40])[CH2:46][CH2:45]5)[CH:48]=4)[N:39]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: Fc1ccc(CNc2cccn3nc(Cl)nc23)cc1
Agent: Clc1nc2c(Br)cccn2n1
Agent: NCc1ccc(F)cc1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccc(F)cc5)cccn4n3)c2)CC1

Procedure:
2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-fluoro-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol), and 4-fluorobenzylamine (1.11 mL, 9.72 mmol) in a manner analogous to Example 2d. Product isolated as an off-white solid, (1.94 g. 82%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.08 (d, J=6.5 Hz, 1H), 7.42 (m, 2H), 7.29 (m, 1H), 7.13 (t, J=17.1, 8.6 Hz, 2H), 6.95 (t, J=14.7, 7.3 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H). 396b) N(8)-(4-Fluoro-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-fluoro-benzyl)-amine (0.288 g, 1.04 mol) and 3-(4-methylpiperazin-1-yl)aniline (223 mg, 1.17 mol) in a manner analogous to Example 2d. Product isolated as red foam (83.06 mg, 18.5%). 1H NMR (400 MHz, (D3C)2SO, δ, pap): 9.16 (s, 1H), 7.96 (d, J=6.3 Hz, 1H), 7.43 (t, J=12.8, 6.7 Hz, 2H), 7.26 (m, 2H), 7.18-7.06 (m, 3H), 6.72 (t, J=14.3, 7.2 Hz, 1H), 6.45 (m, 2H), 6.32 (d, J=8.4 Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 3.11 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=432 (MH)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:9]1[CH:8]=[C:7](/[CH:6]=[CH:5]/[CH2:4][CH2:3][CH2:2][N:19]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[O:15][CH3:16]
Reactant: C1CNCCNC1
Reactant: COc1cc(/C=C/CCCBr)cc(OC)c1OC
Product: COc1cc(/C=C/CCCN2CCCNCC2)cc(OC)c1OC

Procedure:
(E)-5-Bromo-1-(3,4,5-trimethoxyphenyl)-1-pentene (434 mg) and homopiperazine (276 mg) were reacted in the same manner as in Preparation Example 4 to obtain the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([OH:23])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=S)C=CC=CC=1>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([OH:23])[C:8]2=[S:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1c(O)c(CCCCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Product: Oc1c(CCCCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 121.3 %

Procedure:
Reaction of 159d (0.025 g, 0.077 mmol) and P4S10 (0.020 g, 0.046 mmol) under neat conditions as described for synthesis of 162b gave compound 162d (0.019 g, 73%) as a olive green solid. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=2.9 Hz, 2H), 7.83 (t, J=7.8 Hz, 3H), 7.43 (q, J=7.4 Hz, 2H), 7.32 (t, J=6.6 Hz, 1H), 7.08 (m, 1H), 6.92 (dd, J=31.0, 6.8 Hz, 1H), 6.81 (m, 1H), 4.51 (m, 2H), 4.41 (t, J=7.0 Hz, 2H), 1.89 (m, 4H), 1.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 168.37, 155.10, 147.66, 131.04, 130.46, 128.75, 128.05, 125.57, 119.68, 113.69, 111.96, 57.73, 49.73, 29.47, 27.12, 23.04. HRMS (EI) calcd for C18H20N4OS [M]+ 340.135. found 326.1364.
Reaction SMILES: [N+:1]([C:4]1[CH:57]=[CH:56][C:7]([O:8][P:9]2([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:14]=[P:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[P:11]([O:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=3)([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].CCCCCC>NC1C=CC=CC=1.[Pt]=O>[NH2:1][C:4]1[CH:57]=[CH:56][C:7]([O:8][P:9]2([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:14]=[P:13]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=3)([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[P:11]([O:39][C:40]3[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=3)([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:10]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OP2(Oc3ccccc3)=NP(Oc3ccccc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccccc3)(Oc3ccc([N+](=O)[O-])cc3)=N2)cc1
Agent: O=[Pt]
Solvent: Nc1ccccc1
Solvent: CCCCCC
Product: Nc1ccc(OP2(Oc3ccccc3)=NP(Oc3ccccc3)(Oc3ccc(N)cc3)=NP(Oc3ccccc3)(Oc3ccc(N)cc3)=N2)cc1
Temperature: 50 °C
Yield: 70.1 %

Procedure:
A 250-ml heater-equipped autoclave pressure bottle was charged with a solution of 20 (16.0 g) in aniline (40 ml), containing catalyst platinum oxide (0.075 g). The mixture was agitated vigorously at 50° C. and 60 psi of hydrogen until no further pressure drop was observed (3-4 h). The reaction mixture was filtered and concentrated under reduced pressure to 10 ml and poured slowly into hexane. The hexane was decanted off. The light brown paste was then extracted with hot hexane until the maceration was difficult. The thick paste was cooled in ice to give a light-yellow solid, which recrystallized from o-dichlorobenzene to give a white solid. The solid was further boiled with n-hexane, filtered, and dried to yield 21 (10.0 g). DTA examination of this solid showed a melting point range from 115°-145° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[Na+].[OH-].[Na+].Cl[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: OCCCCCCCCCl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCCCCCCCOc1ccccc1-c1ccccc1

Procedure:
The compound was prepared using essentially the procedure of Preparatory Example 1 with 2-hydroxy biphenyl (40 g.), water (250 g.), sodium iodide (3.5 g.) and sodium hydroxide (37.6 g. of 50% in water). This mixture was heated to 100° C. with agitation and 8-chloro-1-octanol (77.4 g.) was added. The product was recovered essentially as in Preparatory Example 1.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:23])[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10](=[O:23])[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1c(CC(O)CO[Si](C)(C)C(C)(C)C)ccc2c1COC2=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1c(CC(=O)CO[Si](C)(C)C(C)(C)C)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)-4-methylisobenzofuran-1(3H)-one (1.00 g, 3.0 mmol) in CH2Cl2 (30 mL) was added Dess-Martin periodinane (6.30 g, 15.0 mmol). After stirring at 25° C. for 12 h, the reaction mixture was filtered through a short pad of SiO2 with CH2Cl2 (100 mL) as the eluting solvent. After concentrating, the residue was purified by flash column chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
A solution of 5-bromo-2-chloropyridin-3-amine (1.0 g, 4.8 mmol) and diisopropylethylamine (1.85 mL, 10.6 mmol) in dichloromethane (25 mL) was cooled to 0° C., and then methanesulfonyl chloride (750 uL, 9.6 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 15 min and was then warmed to rt. After stirring for 2 h, water was added, and then the biphasic mixture was partitioned. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was then dissolved in dioxane (10 mL) and water (10 mL). Potassium carbonate (2.76 g, 20 mmol) was added, and the reaction mixture was stirred for 15 h at rt. Water was then added to the mixture which was subsequently acidified with aqueous citric acid (10%). The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient, 100% hexanes to 50% hexanes:50% ethyl acetate) to provide N-(5-bromo-2-chloropyridin-3-yl)methanesulfonamide (520 mg, 1.82 mmol, 38% yield) as a light pink solid. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, 1H), 8.14 (d, 1H), 6.83 (br s, 1H), 3.11 (s, 3H); MS (EI) for C6H6BrClN2O2S: 285, 287, 289 (Br+Cl isotopes, MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([C:47]([F:50])([F:49])[F:48])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(C(F)(F)F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid gave 268. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.38 (t, J=7.5 Hz, 1H), 7.90-7.75 (m, 2H), 7.62-7.50 (m, 3H), 5.05-4.71 (m, 2H), 4.22-4.06 (m, 1H), 4.05-3.92 (m, 1H), 3.75 (s, 3H), 3.34-3.21 (m, 1H), 2.18-2.10 (m, 1H), 1.88-1.72 (m, 4H), 1.69-1.60 (m, 1H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: N.Cl[C:3]1(Cl)[C:5]([CH3:7])([CH3:6])[CH:4]1[CH2:8][CH2:9][C:10]([CH3:14])([OH:13])[C:11]#[CH:12].[Na]>CCOCC>[CH3:6][C:5]1([CH3:7])[CH2:3][CH:4]1[CH2:8][CH2:9][C:10]([CH3:14])([OH:13])[C:11]#[CH:12]
Reactant: C#CC(C)(O)CCC1C(C)(C)C1(Cl)Cl
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: C#CC(C)(O)CCC1CC1(C)C
Yield: 86.4 %

Procedure:
Ammonia, 1 l, is placed in a reaction flask. A solution of 150 g (0.63 mol) of 5-(2',2'-dichloro-3',3'-dimethylcyclopropyl)-3-methyl-1-pentyn-3-ol dissolved in 750 ml of ether is added dropwise. Sodium (62 g, 2.7 mol) in small portions is added at -30° to -35° within 21/2 hours until the blue coloration persists. The ammonia is evaporated and 1.5 liters of hexane are added dropwise followed by the addition of 100 ml of ethanol. The reaction mixture is poured into a mixture of 150 ml of acetic acid in 500 g of ice, washed neutral in succession with water, saturated sodium carbonate solution, saturated sodium chloride solution, dried and evaporated. The crude product (100.2 g) is distilled. In this manner there are obtained 90.5 g (85%) of 5-(2',2'-dimethylcyclopropyl)-3-methyl-1-pentyn-3-ol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].O1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C([O-])([O-])=O.[Na+].[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]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:6]3[CH:5]=[CH:4][C:9]([CH3:8])=[C:47]([O:48][C:49]4[CH:50]=[CH:21][CH:22]=[CH:13][CH:11]=4)[CH:46]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: Cc1ccc(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cc1Oc1ccccc1

Procedure:
A mixture of EXAMPLE 30A (172 mg), EXAMPLE 108A (74 mg), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg) in dioxane (6 mL) and 2M aqueous Na2CO3 solution (3 mL) was stirred at 60° C. for 18 hours. The mixture was chromatographed on silica gel using 2-20% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Br:15])=[CH:14][C:9]=2[CH:8]=[C:7]([C:16]([O:18]CC=C)=[O:17])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N1CCOCC1.O.Cl>O1CCCC1.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>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Br:15])=[CH:14][C:9]=2[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=Cc2cc(Br)ccc2N(CC=C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: C=CCN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of allyl 1-allyl-7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (224 mg) in tetrahydrofuran (10 ml) were added tetrakistriphenylphosphinepalladium (74 mg) and morpholine (560 mg), and the mixture was stirred under argon atmosphere at room temperature for 2 hours. To the mixture was added water at 0° C., and the mixture was made acidic (pH=4) with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, further with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-allyl-7-bromo-2,3-dihydro-1-benzazepine-4-carboxylic acid (198 mg) as yellow amorphous.
Reaction SMILES: C(OC([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:7]1=[O:36])=O)C.[OH-].[Na+]>CO>[Cl:35][C:32]1[CH:33]=[C:34]2[NH:6][C:7](=[O:36])[C:8]3([CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:29]2=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester prepared in example 4c (0.45 g, 0.92 mmol) in methanol (30 mL) was added NaOH (66 mg, 1.65 mmol). The mixture was stirred at room temperature for 0.5 h. The solvent was removed and the residue was partitioned between ethyl acetate and aqueous HCl solution (1 N). The aqueous layer was extracted with ethyl acetate. The organic layers were combined and then concentrated. The residue was purified with chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione as a white solid (Yield 0.2 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[N+:10]([O-])=[CH:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])cc[n+]2[O-])cc1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2cc([N+](=O)[O-])ccn2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a 2 L 3 neck round bottom flask fitted with a mechanical stirrer, was added N-(4-methoxybenzyl)-4-nitropyridin-2-amine 1-oxide (38.72 g, 0.14 mol) and chloroform (580 mL). The reaction mixture was cooled to 0° C. and phosphorus trichloride (36.8 mL, 0.42 mol) was added dropwise. The reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was filtered and the resulting solid was slurried with hexanes and filtered (repeated several times) to afford N-(4-methoxybenzyl)-4-nitropyridin-2-amine (39.34 g, 102%) as a yellow solid. LCMS: (FA) ES+ 260; 1H NMR (400 MHz, CD3OD) δ ppm 8.20 (d, J=5.9 Hz, 1H), 7.33-7.25 (m, 1H), 7.22 (dd, J=5.9, 2.0 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 4.51 (s, 1H), 3.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:23]#[N:24])[CH2:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][CH:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:8]1)[CH3:2].Br.C(O)(=[O:29])C>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:9]2[CH2:10][CH2:11][C:12]3[NH:24][C:23](=[O:29])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH2:6][C:7]=3[CH2:8]2)=[CH:16][CH:17]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C#N)CC1CC(Cc2ccc(OC)cc2)CCC1=O
Agent: Br
Product: CCOC(=O)C1CC2=C(CCC(Cc3ccc(OC)cc3)C2)NC1=O
Reaction time: 0.5 h

Procedure:
2-Cyano-3-(3-(4-methoxyphenyl)methyl-6-oxocyclohexanyl)propanoic acid ethyl ester (2.43 g) was added to 15% w/v solution of HBr in acetic acid at 5° C. and stirred for 30 minutes. The reaction mixture was evaporated under reduced pressure and washed with saturated sodium carbonate solution. The mixture was extracted into ethyl acetate and the organic phase dried (MgSO4) and evaporated. The residue was diluted with diethyl ether and allowed to crystallise to give the title compound (0.5 g) mp. 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.ClS([N:35]=[C:36]=[O:37])(=O)=O.Cl>C(Cl)Cl>[C:25]1([C:22]2[CH:23]=[CH:24][N:10]3[C:11]=2[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:36]([NH2:35])=[O:37])[CH:7]=[N:6][CH:5]=2)=[N:9]3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: NC(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.100 g, 0.254 mmol) (prepared as in Example 3) was dissolved in CH2Cl2 (10 mL) and chlorosulfonyl isocyanate (0.0330 mL, 0.381 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Concentrated hydrochloric acid was added until the reaction mixture forms a clear solution. The aqueous mixture was extracted with CH2Cl2 (30 mL) and the organic layer was separated. The aqueous layer was adjusted to pH 11 using saturated solution of sodium hydroxide. The aqueous solution was extracted with CH2Cl2 (20×3 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-62 as described in general methods) to obtain 1-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)urea (30.0 mg, 27.0%). LCMS Condition B-14: retention time 1.831 min, [M+1]=437.2. HPLC Condition B-30: retention time 5.48 min, Purity 95.9%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.91 (d, J=4.8 Hz, 2H), 6.05 (br s, 2H), 6.81 (d, J=2.4 Hz, 1H), 7.27 (t, J=4.8 Hz, 2H), 7.46-7.61 (m, 7H), 7.76 (dt, J=1.6 Hz, J=7.6 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 8.38-8.39 (m, 1H), 8.66-8.68 (m, 1H), 8.88 (s, 1H), 8.96 (d, J=1.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([NH:14][CH2:15][CH2:16][C:17](O)=[O:18])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[C:10]([O:9][C:7]([NH:14][CH2:15][CH2:16][C:17]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:18])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 127 %

Procedure:
To a mixture of 2-amino-2-methyl-1-propanol (177.4 mg; 1.99 mmol; 1 eq) and boc-beta-alanine (338.9 mg; 1.79 mmol; 0.9 eq) in DCM (30 ml), are added triethylamine (0.83 ml; 5.97 mmol; 3 eq) and 2-chloro-1-methylpyridinium iodide (1525 mg; 5.97 mmol; 3 eq). The mixture is stirred for 2 days at RT. The reaction is followed by TLC (cyclohexane/EtOAc 1:1). The reaction mixture is then washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layer is dried over Na2SO4, filtered and concentrated to give 592 mg of an orange oil, which is purified by flash chromatography (cyclohexane/EtOAc gradient, from 9/1 to 1/1 over 30 min). The title compound is isolated as a slightly yellow solid (331.1 mg; 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([C:17]#[N:18])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>C(OCC)C.C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:17](=[NH:18])[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[CH:15]=[CH:16][C:7]([NH:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=2[O:2][CH3:1])=[N:8]3)=[CH:26][CH:25]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COc1ccccc1CNc1ccc2c(C#N)cccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1CNc1ccc2c(C(=N)c3ccc(F)cc3)cccc2n1
Temperature: 0 °C
Yield: 41.3 %

Procedure:
To a cooled (ice bath) and stirred suspension of 2-(2-methoxy-benzylamino)-quinoline-5-carbonitrile (289 mg, 1.0 mmol) in diethylether (3 ml) and THF (1 ml) was added drop wise a 1M solution of 4-fluorophenyl-magnesium bromide (4 ml, 4.0 mmol), the reaction mixture was heated under reflux conditions for 24 h and poured into ice-water (15 ml). 2N HCl (5 ml) was added, the mixture was stirred at room temperature for 10 min, 3 N NaOH (5 ml) was added and the mixture was extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (2×20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white solid (159 mg, 41%).