Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:10](OC)(OC)OC.[ClH:17]>CC(C)=O>[ClH:17].[N:1]1[C:2]2([CH2:6][CH2:5][CH2:4][CH2:3]2)[C:7](=[O:8])[NH:9][CH:10]=1
Reactant: NC(=O)C1(N)CCCC1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=C1NC=NC12CCCC2
Yield: 92.2 %

Procedure:
20 g (0.156 mol) of 1-aminocyclopentane-1-carboxamide and 28 g (0.19 mol) of trimethyl orthoformate are refluxed for 1 hour. The condenser is then changed to a "No hold up" condenser, and the temperature is elevated to 140° C. inner temperature. The residue is dissolved in 150 ml of acetone the pH is adjusted to 1-2 with concentrated hydrochloric acid and after cooling the resulting suspension the product is filtered of. 25 g of the title compound is obtained, yield 92.2%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.N[C@H](C(OC(C)(C)C)=O)CC1C=CC=CC=1.C([BH3-])#N.[Na+].[ClH:30].N1C=CC=CC=1>CO>[ClH:30].[OH:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: c1ccncc1
Product: OC1CN2CCC1CC2
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 9.00 g (56.25 mmol) 3-quinuclidinone and 4.15 g (18.75 mmol) Phe-O-t-Bu in 50 ml methanol was added over a 12 hour period a solution of 2.95 g (46.9 mmol) sodium cyanoborohydride in 13 ml methanol. After stirring for an additional 8 hours, 5.78 g (50.0 mmol) pyridine hydrochloride was added and after 11/2 hours stirring, sodium chloride was removed by filtration. The filtrate was concentrated to a foam which was treated with 15 ml methanol and 50 ml ethyl acetate to give a slurry of the byproduct 3-hydroxy quinuclidine hydrochloride (74% of excess) which was removed by filtration. The filtrate was concentrate to an oil and charged with 10 ml methanol to a 5×200 cm column of LH-20 and eluted with methanol. The product fraction contained 6.54 g of a mixture of diastereomers in a 55:45 ratio as established by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[F:17][CH:18]([F:28])[C:19]1[C:23]([C:24](Cl)=[O:25])=[CH:22][N:21]([CH3:27])[N:20]=1>N1C=CC=CC=1>[F:28][CH:18]([F:17])[C:19]1[C:23]([C:24]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)=[O:25])=[CH:22][N:21]([CH3:27])[N:20]=1
Reactant: Nc1ccccc1-c1cc(F)c(F)c(F)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)Nc2ccccc2-c2cc(F)c(F)c(F)c2)c(C(F)F)n1
Temperature: 45 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
9.55 kg 3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl-amine (I) were dissolved in 51.4 kg and 6 kg pyridine were added. The mixture was stirred at 45° C. and 8.3 kg 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (II) were dosed during one hour. Due to the exothermic nature of the reaction, the temperature raised to 55° C. Post-reaction by stirring for 1 hour at 55° C. followed. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter deionized water followed. The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C. Around 75° C., the first turbidity was observed, and at 75° C. and 73° C., respectively, the batch was seeded with 10 g 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) each (>98% form B). The resulting slurry was filtered at 0° C. over a process filter and the filter cake was washed with 10 kg toluene at 0° C. After drying in the drying cabinet at 80° C. and 20 mbar for 12 hours, 13.5 kg 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) of >99.5% purity (GC, HPLC, NMR) was isolated. Using powder diffractometry (PXRD) and Fourier-Transform solid state infrared spectrometry (FT-IR) it was proven that the material consists to >98% of form B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([OH:44])[CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH2:41][CH:40]([OH:44])[CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: OC1CCCNC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCC(O)C3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperidin-3-ol according to conditions described in general procedure C. Mp: 180-181° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.26-1.31 (m, 2 H), 1.54 (s, 2 H), 1.81-1.83 (m, 2 H), 2.70-2.82 (m, 2 H), 3.27 (t, J=4.4 Hz, 4 H), 3.36 (s, 2 H), 3.77 (t, J=4.8 Hz, 4 H), 4.22 (bs, 1 H), 4.82 (s, 1 H), 6.16 (d, J=5.1Hz, 1 H), 7.03-7.06 (m, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1 H), 7.50 (s, 1 H), 7.55-7.63 (m, 3 H), 7.84-7.87 (m, 1 H), 7.99-8.01 (m, 1 H), 8.25 (d, J=5.8 Hz, 1 H), 10.49 (s, 1 H).
Reaction SMILES: O1C2C(=CC=CC=2)[C@H](N[C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C@H:24]4[CH2:28][C@@H:27]([C:29](=[O:41])[NH:30][C@H:31]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH2:34][CH2:33][CH2:32]5)[N:26]([C:42](=[O:55])[C@@H:43]([NH:48][C:49](=[O:54])[C@@H:50]([NH:52][CH3:53])[CH3:51])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:25]4)=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:56](=[O:69])[C@@H:57]([NH:62][C:63](=[O:68])[C@@H:64]([NH:66][CH3:67])[CH3:65])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:13])CC1.[CH3:70][C:71]1[O:75][N:74]=[C:73]([C@@H:76]([NH2:84])[CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[N:72]=1.C(O)(C(F)(F)F)=O>>[CH3:61][C:58]([CH3:59])([CH3:60])[C@H:57]([NH:62][C:63](=[O:68])[C@@H:64]([NH:66][CH3:67])[CH3:65])[C:56]([N:15]1[C@H:14]([C:12]([NH:84][C@H:76]([C:73]2[N:72]=[C:71]([CH3:70])[O:75][N:74]=2)[CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[O:13])[CH2:23][C:22]2[C:17](=[CH:18][C:19]([C@H:24]3[CH2:28][C@@H:27]([C:29](=[O:41])[NH:30][C@H:31]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34][CH2:33][CH2:32]4)[N:26]([C:42](=[O:55])[C@@H:43]([NH:48][C:49](=[O:54])[C@@H:50]([NH:52][CH3:53])[CH3:51])[C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:25]3)=[CH:20][CH:21]=2)[CH2:16]1)=[O:69]
Reactant: Cc1nc([C@@H](N)Cc2ccccc2)no1
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCOc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H](Cc1ccccc1)c1noc(C)n1)C(C)(C)C
Yield: 33 %

Procedure:
Following procedures analogous to those described for the preparation of Example 33, (S)-2-(tert-butoxycarbonyl)-7-((3R,5S)-1-(tert-butoxycarbonyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Compound F of Example 33, 60 mg, 0.10 mmol) and (S)-1-(5-methyl-1,2,4-oxadiazol-3-yl)-2-phenylethanamine, TFA (31 mg, 0.10 mmol) were converted to the title compound (34 mg, 33% over 6 steps). MS (ESI+) m/z 1001.7 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=3)[NH:13][N:12]=2)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(C#N)CC3CCCCC3)n[nH]c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CC(CC1CCCCC1)c1n[nH]c2cc(O)ccc12
Temperature: 50 °C
Yield: 51 %

Procedure:
3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile (1.61 g, 5.68 mmol) was dissolved in CH2Cl2 and cooled with an ice bath. BBr3/CH2Cl2 1M (8.6 ml, 8.52 mmol) was added to this mixture, which was stirred at 50° C., then poured onto saturated NaHCO3 solution, extracted with ethylacetate, dried over Na2SO4, filtered, concentrated under vacuum and purified by flash chromatography (CH2Cl2/MeOH 98/2). Crystallisation from EtOH gave 780 mg of white crystals (51%). mp 175° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:17]=[C:16](O)[CH:15]=[C:14]([CH3:19])[N:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:16]1[CH:15]=[C:14]([CH3:19])[N:13]=[C:12](/[CH:11]=[CH:10]/[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Product: Cc1cc(Cl)nc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Yield: 70.4 %

Procedure:
In analogy to example 12c), by heating was (E)-2-[2-(3-nitro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (1.28 g, 5 mmol) in POCl3 (9.16 ml, 0.1 mol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(3-nitro-phenyl)-vinyl]-6-methyl-pyrimidine (0.97 g, 71%) as an off-white solid. EI mass spectrum, m/e: 275 (M calculated for C13H10ClN3O2: 275).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([CH:27]([OH:32])[C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)C(F)(F)F)cc2)c1Sc1ccc(Cl)cc1
Solvent: CCO
Product: Cn1c(-c2ccccn2)nc(-c2ccc(C(O)C(F)(F)F)cc2)c1Sc1ccc(Cl)cc1

Procedure:
The title compound was prepared from 1-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}phenyl)-2,2,2-trifluoroethanone (Example 58) following the procedure described for Example 55. 1H NMR (500 MHz, (CDCl3): 8.64 (broad s, 1H), 8.39 (broad d, 1H), 7.84 (t, 1H), 7.36 (t, 1H), 7.25 (d, 2H), 7.23 (d, 2H), 7.06 (d, 2H), 7.03 (d, 2H), 4.59 (m, 1H), 4.15 (s, 3H). LCMS: m/z 476 (M+H)+.)+. The racemic alcohol was resolved on a Chiral OJ column (20% EtOH/80% hexanes, flow rate 1 mL/min) to give two enantiomers: faster enantiomer's retention time=15.8 min; slower enantiomer's retention time=18.9 min.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:37])=[C:5]([C:28]([O:35]C)=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:32][O:31][C:30]1[C:3](=[O:2])[C:4]([CH3:37])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:28](=[O:35])[C:29]=1[O:33][CH3:34]
Reactant: COc1c(C)c(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 63.2 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyloxy)benzoyl]morpholine (0.042 g, 0.0827 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.113 g, 0.207 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate:methanol=3:6:1) to obtain the titled compound (0.025 g, 0.0523 mmol, 63%).
Reaction SMILES: [C:1]1([N:7]2[N:11]3[C:12](=[O:19])[C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=[C:10]3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.O1[CH2:29][CH2:28]OCC1>>[C:1]1([N:7]2[N:11]3[C:12](=[O:19])[C:13]([C:16]([O:18][CH2:2][CH2:1][N:7]([CH2:28][CH3:29])[CH2:8][CH3:9])=[O:17])=[CH:14][N:15]=[C:10]3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cnc2ccn(-c3ccccc3)n2c1=O
Reactant: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCN(CC)CCOC(=O)c1cnc2ccn(-c3ccccc3)n2c1=O

Procedure:
1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.2 g) was reacted with thionyl chloride (0.8 ml) in dioxane (30 ml) at the reflux temperature for 3 hours, then the mixture was evaporated in vacuo to dryness. The residue was dissolved in dioxane (30 ml) and reacted with 2-(diethylamino)-ethanol (1.2 g) at room temperature for 24 hours. After dilution with water and alkalinization with Na2CO3 the precipitate was extracted with ethyl acetate: evaporation to dryness and crystallization from chloroformethanol gave 0.7 g of 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, 2-(diethylamino)-ethyl ester, m.p. 127°-130° C.
Reaction SMILES: C1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]([O:13][CH:14]=C)[CH2:9][CH2:10][CH:11]=C)C=CC=CC=1.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH:7]([CH:8]1[CH2:9][CH2:10][CH:11]=[CH:14][O:13]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CCCC(OC=C)C(c1ccccc1)c1ccccc1
Reactant: c1ccccc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Product: C1=COC(C(c2ccccc2)c2ccccc2)CC1
Yield: 92.6 %

Procedure:
A solution of 1,1-diphenyl-2-(1-ethenoxy)-hex-5-ene 9 (5.1 g, 18.3 mmol) and Grubb's catalyst (1.5 g, 1.83 mmol) in benzene (200 ml) was heated under reflux for 20 hr. The solvent was removed under vacuo and the residue was chromatographed over silica gel (Hexane/Ethyl Acetate 20:1) to give 2-diphenyl-3,4-dihydro-2H-pyran 10 (4.25 g, 92.6%) as a liquid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][Si:7]([CH3:22])([CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:15][O:14]1>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:15][CH:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:7]([CH3:22])([CH3:6])[CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:2]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C
Temperature: 60 °C

Procedure:
Diethylamine (2.66 g, 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 60° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 60° C. for an additional 8 hours. Ethanol and diethyl amine were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)([CH3:41])[CH3:40]>>[NH2:30][C:29]1[S:28][C:27]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([CH:39]([CH3:41])[CH3:40])[CH:47]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: CC(C)c1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-isopropylbenzeneboronic acid gave 301 as the mono-formate salt as a red gum (38 mg, 41% over two steps). 1H NMR (400 MHz, d6-DMSO with D2O) δ 8.35 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.32-7.25 (m, 2H), 3.62 (s, 3H), 3.10 (d, J=11.5 Hz, 2H), 3.04-2.88 (m, 3H), 2.72 (d, J=6.9 Hz, 2H), 1.73 (d, J=12.6 Hz, 2H), 1.64-1.58 (m, 1H), 1.34-1.24 (m, 2H), 1.22 (d, J=6.9 Hz, 6H). LCMS (ES+) m/z 454 (M+1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O[CH2:21][CH:22]([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:27]([O:26][C:25]([NH:24][CH2:23][CH:22]([CH3:32])[CH2:21][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:31])([CH3:30])([CH3:29])[CH3:28].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(CO)CNC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)CNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 1.9 g, 7.4 mmol), tert-butyl (3-hydroxy-2-methylpropyl)carbamate (2.8 g, 14.8 mmol) and triphenylphosphine (4.9 g, 18.5 mmol) in THF (35 mL) at 0° C. is added diisopropyl azodicarboxylate (3.8 mL, 18.5 mmol). The mixture is stirred for 16 h at room temperature and then the solvent is removed. The residue is filtered through a pad of silica (300 g, 240-400 mesh) using 30% EtOAc in heptane to afford of mixture of the title compound and diethyl 1H-indole-2,6-dicarboxylate (3.2 g) which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[OH:9][C:10]([CH3:22])([CH3:21])[C@H:11]([C:13]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14])[NH2:12].Cl.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[Br:8][C:6]1[CH:7]=[C:2]([NH:12][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[O:14])[C:10]([OH:9])([CH3:21])[CH3:22])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(O)[C@@H](N)C(=O)NCC(F)(F)F
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: CC(C)(O)[C@@H](Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Temperature: 80 °C

Procedure:
To a mixture of 3,5-dibromopyridine (378 mg, 1.6 mmol), 3-hydroxy-N-(2,2,2-trifluoroethyl)-D-valinamide.HCl I-27b (400 mg, 1.6 mmol), potassium carbonate (882 mg, 6.38 mmol) and L-proline (36.7 mg, 0.319 mmol), in DMSO (5 mL) and degassed with nitrogen was added copper(I) iodide (STREM crushed) (30.4 mg, 0.160 mmol). The reaction was sealed and heated at 80° C. for 64 h. The reaction was quenched into water and extracted with DCM. The organic layer was washed with aq. NaHCO3, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (EtOAc/hexane; 25-100%) to afford the title compound I-27. MS APCI: [M+H]+ m/z=371.1. 1H NMR (600 MHz, DMSO) δ 8.57 (t, J=6.5 Hz, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.17 (s, 1H), 6.17 (d, J=6.5 Hz, 1H), 4.77 (s, 1H), 3.85 (m, 2H), 3.80 (d, J=6.5 Hz, 1H), 1.07 (s, 3H), 1.06 (s, 3H).
Reaction SMILES: [Cl-].[CH:2]1([CH2:5][NH2+:6][CH2:7][CH2:8]Cl)[CH2:4][CH2:3]1.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]=[S:22]>>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]1[N:6]([CH2:5][CH:2]2[CH2:4][CH2:3]2)[CH2:7][CH2:8][S:22]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]CC1CC1
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][CH:33]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:25]4=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][N:24]4[N:23]=[CH:22][N:21]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][C@H:43]([CH2:47]O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([CH2:47][O:30][CH2:29][C:26]2[CH:27]=[CH:28][N:24]3[C:25]=2[C:20]([NH:19][C:15]2[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=2)[N:10]([CH2:9][C:8]2[CH:31]=[CH:32][CH:33]=[C:6]([F:5])[CH:7]=2)[N:11]=[CH:12]4)=[N:21][CH:22]=[N:23]3)[CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: OCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(COCc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1
Reaction time: 0.2 h
Yield: 49.8 %

Procedure:
Thionyl chloride (18 μL, 1.1 equiv) was added to a solution of {4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methanol (80 mg, 0.205 mmole) in dry DCM (4 mL) at RT. After 12 min, (2S)-2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (65.3 mg, 1.5 equiv, H. Yanagisawa et al., Heterocycles, 1993, 35, 105.) was added followed by DIPEA (39.5 μL, 1.1 equiv). After 72 hr at RT, the solvent was removed and silica gel chromatography of the residue (gradient elution with 0 to 50% EtOAc in hexane) afforded 2-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl}-morpholine-4-carboxylic acid tert-butyl ester (60 mg, 50% yield); MS: 588 (M+H)+; HPLC Ret Time: 2.69 min (Xterra C18 S5, 3.0×50 mm, 3 min gradient, 4 mL/min. A solution of this material in DCM (2 mL) was cooled to 0° C. and treated with TFA (1 mL). After 90 min, the solvents were removed and the residue was dissolved in DCM. This was washed with saturated NaHCO3 solution and the organic phase was dried (Na2SO4) and the solvents removed. Purification by preparative HPLC and then radial chromatography (1 mm silica gel plate, gradient elution with 0 to 3% NH3 (2N in MeOH) in DCM gave the title compound (30 mg, 60% yield): 1H NMR (CDCl3) δ 2.84-2.58 (m, 4H), 3.65-3.35 (m, 4H) 3.65-3.35 (m, 4H), 4.87 (s, 2H), 5.58 (s, 2H), 6.54 (d, J=2.5 Hz, 1H), 6.83 (d, J=9.5 Hz, 1H), 6.98-6.90 (m, 2H), 7.32-7.20 (m, 3H), 7.48 (d, J=2.5 Hz, 1H), 7.58 (dd, J=1.8, 8.8 Hz, 1H), 7.94 (s, 1H), 8.19 (s, 1H), 9.58 (s, 1H); MS: 488 (M+H)+; HPLC Ret Time: 1.65 min (Xterra C18 S5, 3.0×50 mm, 3 min gradient, 4 mL/min).